Model studies in the lepadin series: Synthesis of enantiopure decahydroquinolines by aminocyclization of 2-(3-aminoalkyl)cyclohexenones

Article abstract of DOI:10.1016/j.tet.2005.06.024

Syntheses of enantiopure 3-acetoxy-2-methyldecahydroquinolines are accomplished by coupling cyclohexenyllithium 3 with α-amino epoxides and an aminocyclization of 2-(3-aminoalkyl)cyclohexenones (i.e., 5 and 9) as the key steps. The procedure allows the incorporation of alkyl substituents at C(5) to give enantiopure 2,3,5-trisubstitued decahydroquinolines.

Full text of DOI:10.1016/j.tet.2005.06.024

Tetrahedron 61 (2005) 8264–8270
Model studies in the lepadin series: synthesis of
enantiopure decahydroquinolines by aminocyclization
of 2-(3-aminoalkyl)cyclohexenones
*
Marisa Mena and Josep Bonjoch
´ ` `
Laboratori de Quımica Organica, Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIIIs/n, 08029-Barcelona, Spain
Received 2 May 2005; revised 3 June 2005; accepted 8 June 2005
Abstract—Syntheses of enantiopure 3-acetoxy-2-methyldecahydroquinolines are accomplished by coupling cyclohexenyllithium 3 with
a-amino epoxides and an aminocyclization of 2-(3-aminoalkyl)cyclohexenones (i.e., 5 and 9) as the key steps. The procedure allows the
incorporation of alkyl substituents at C(5) to give enantiopure 2,3,5-trisubstitued decahydroquinolines.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
methyldecahydroquinolines in these synthetic approaches
involve the elaboration of a polyfunctionalized piperidine
followed by carbocyclic ring closure through aldol
processes5,6 or the construction of the piperidine ring from
cyclohexanone derivatives either by an intramolecular
enamine alkylation7 or using a xanthate-mediated radical
cyclization8 (Scheme 1).
Lepadin alkaloids are structurally characterized by the
presence of a 2,3,5-trisubstituted cis-fused decahydroquino-
line ring. The substitution pattern, which has a methyl group
at C(2), a hydroxyl group, free or acylated, at C(3), and an
eight carbon side chain at C(5), shows a variety of
stereochemical arrangements, as shown in Figure 1. Eight
lepadins (A–H) have been isolated from marine sources
since 1991,1–4 of which lepadins A–C have been found to
possess significant in vitro cytotoxicity against several
human cancer cell lines, whereas lepadins D–F have shown
low cytotoxicity but significant and selective antiplasmodial
and antitrypanosomal activity.
In this work, we report our studies on a new synthetic entry
to the azabicyclic core of lepadins, either those that show a
cis or trans relationship between the respective methyl and
hydroxyl substituents at C(2) and C(3) of the decahydro-
quinoline ring (see Fig. 1). In our approach, we envisaged
enantiopure cyclohexenones of type I (R0ZH) as potential
intermediates as they would bring about ring closure by
forming the N–C(8a) bond. Here, we present the synthesis
of these building blocks and the results o0btained by their
aminocyclization, either when R0ZH or R Zalkyl.
2. Results and discussion
2.1. Synthetic aspects
Figure 1.
Total enantioselective syntheses of lepadins A,5 B,5–7 C,5
D–E,7 and H,7 as well as a formal route to rac-lepadin B8
have been reported. The strategies described for the
The required starting materials are 2-bromocyclohex-2-
enone ethylene acetal (1) and the (S) and (R) isomers of [(S)-
10-(dibenzylamino)ethyl]oxirane (2a and 2b). The cyclo-
hexenone derivative 1, reported by Smith,9 is a precursor of
the a-ketovinyl anion equivalent 3, often used in the
formation of C–C bonds, for example, in reactions with
alkyl halides,9,10 ketones,11 ethyl chloroformate,9 and
DMF.12 Moreover, this vinyllithium derivative has been
construction
of
5-substituted
3-hydroxy-2-
Keywords: Lepadin alkaloids; Decahydroquinolines; Epoxides; Organo-
lithiums; Nitrogen heterocycles.
*
Corresponding author. Tel.: C34 934024540; fax: C34 934024539;
e-mail: josep.bonjoch@ub.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.024

M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270
8265
Scheme 1. Synthetic approaches to lepadin alkaloids.
transmetallated with copper,13 tin,14 and palladium15
reagents and then used in coupling processes. Finally, the
lithium compound 3 reacts with TMSCl16 and sulfinates to
give vinylsilane and vinylsulfoxide17 derivatives, respect-
ively. To our knowledge, this versatile lithium derivative
has not been used in reactions with epoxides, such as
described in the present work. On the other hand, epoxides
stereogenic centers are formed, the bicyclic compounds 6a
and 7a were isolated in a 2:1 ratio. We then carried out the
same sequence of reactions but starting from epoxide 2b20
(Scheme 3). In this series, the aminocyclization step starting
from cyclohexenone 5b gave a nearly equimolecular
mixture of decahydroquinolines 6b and 7b. Thus,
5-dealkyllepadin derivatives with the same absolute
configuration as lepadins D, E, and H (i.e., compound 6a),
and lepadins A, B, and C (i.e., compound 6b) were
achieved.
218 have been described by Reetz,19 Barluenga and
20
Concellon and Beaulieu,21 but there are no examples of
´
their reactions with organolithium derivatives.22
The vinyllithium 3 formed on treatment of bromoacetal 1
with n-BuLi in THF reacted with epoxide 2a20 in presence
of BF3$Et2O (Ganem’s conditions)23,24 to give enantiopure
alcohol 4a (Scheme 2). After protection of the hydroxyl
group as an acetate and subsequent deprotection of the
acetal, the resulting cyclohexenone 5a was submitted to a
hydrogenation reaction, which involves a reduction of the
double bond, a double debenzylation of the tertiary amine
and an intramolecular reductive amination, to give the
decahydroquinoline ring. In this process, in which two new
Scheme 3.
At this point, we explored the usefulness of cyclohexenones
5 as precursors of 5-alkylsubstituted decahydroquinolines
(Scheme 4). Treatment of 5a with n-BuLi gave a tertiary
alcohol as an epimeric mixture, which was reacetylated
upon the hydroxyl of the side chain, and the resulting 8a was
oxidized25 to give the rearranged enone 9a. The multi-step
tranformation of 9a under a hydrogen atmosphere (hydro-
genation, debenzylation, and reductive aminocyclization)
gave a mixture of trisubstituted decahydroquinolines 10a
Scheme 2.

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M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270
relationship between the hydrogen atoms of these stereo-
centers suggesting that the double bond underwent a trans
hydrogenation, as has been reported in some tetrasubstituted
alkenes,26 or, after a cis hydrogenation and formation of the
subsequent imine, an epimerization took place at C(4a)
through an enamine intermediate. Again, as occured in the
5-unsubstituted series, the ratio of trans decahydroquino-
lines (i.e., 11b) to the cis epimers was higher in compounds
with a 3S rather than 3R configuration.
2.2. NMR studies of decahydroquinolines 6, 7, 10, and 11
(series a and b)
The cis (6 and 10) and trans decahydroquinolines (7 and 11)
are clearly differentiated by two NMR features: (i) the H
1
NMR chemical shift of H-8a, which appears more deshieled
(d 2.95) in the cis-than in the trans-derivatives (d 2.20); (ii)
the 13C chemical shift of C(7) is more deshielded (w4–
5 ppm) in the trans than in the cis derivatives.27 In all cases,
the preferred conformation of the cis decahydroquinolines
has the H-8a axial with respect to the N-containing ring (N-
endo conformer).
Scheme 4.
and 11a in a nearly equimolecular ratio (71% overall yield),
in which three new stereogenic centers were formed.
Working with the epimeric epoxide 5b, and following the
same reaction sequence, decahydroquinolines 10b and 11b
were formed in a 1:4 ratio (65% overall yield).
The absolute configuration of 6a was deduced considering
that: (a) the coupling constants for H-2 (dq, JZ10, 6.5 Hz)
and H-3 (td, JZ10.5, 4.8 Hz) determined their axial
location and hence, fixed the methyl at C(2) and the acetoxy
at C(3) to an equatorial disposition; (b) the multiplicity of
H-8a (br s) implied an equatorial relationship with respect to
the cyclohexane ring, which discarded not only a trans
junction of the decaline ring but also, taking into account the
preferred conformation, implied an R configuration for
C(8a). The 13C chemical shifts also agree with this
elucidation since the value of d 20.3 for C(7) is diagnostic
of a cis decahydroquinoline in a N-endo conformation. For
trans compound 7a, the axial proton H-8a is strongly
coupled to two adjacent axial protons and one equatorial
proton. Hence, its resonance signal appears as a deceptively
simple triplet (JZ10.4 Hz) of doublets (JZ3.2 Hz)
centered at d 2.19. The NMR data for compounds 6b and
7b follow the same pattern of signals as that of their
corresponding epimers at C(3), the major differences being
in the chemical shift for H-3, which is now more deshielded
since it is located in an equatorial arrangement, and in C-3
and C-4a, which resonate at a lower field, due to the axially
In all the cyclization processes (5/6C7 and 9/10C11),
both in series a (3R configuration) and series b (3S
configuration), the isolated decahydroquinolines show an
R configuration at C(8a) (see Fig. 2). The configuration at
C(4a) is controlled by the configuration of C(3) as well as by
the presence or absence of a substituent at C(5). From the
b-unsubstituted cyclohexenones (i.e., compounds 5), the
aminocyclization takes place with some diastereoselection
if the acetoxy substituent can adopt a pseudo-equatorial
disposition in the transition state leading to the reduced
product, as occurs in 6a, whereas in the epimeric series no
stereocontrol was observed in the formation of the C(4a)
stereocenter. Since it has not been established if the course
of the reaction follows a pathway through an enimine
intermediate or if there is a reduction of the double bond
prior to the cyclization step, a clear understanding of the
stereochemical course is not possible at this stage. More
intriguing is the pathway of the aminocyclization leading to
2,3,5-trisubstituted decahydroquinolines 10 and 11. The
configuration at C(4a) and C(5) in all cases showed a trans
Figure 2. Preferred conformation of decahydroquinolines 6, 7, 10, and 11.

M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270
8267
located acetoxy group (Table 1). For trisubstituted cis
decahydroquinoline 10a, the butyl substituent at C(5)
controls the preferred conformation of the bicyclic ring,
which agrees with the conformation showed for lepadins
where the substituent at C(5) is always equatorially located.
The stereochemistry at C(5) for the butyl substituted
products (10 and 11) was determined considering that the
equatorially located butyl side chain exerts a steric
crowding on H-4eq, due to their 1,3-synperiplanar relation-
ship, which is reflected in the 13C and 1H NMR spectra by an
upfield chemical shift (w3 ppm) for C(4) and a downfield
chemical shift (d 2.25G0.05) for H-4eq as compared to the
NMR data for compounds 6 and 7.
In summary, a new synthetic entry to enantiopure
polysubstituted decahydroquinolines has been reported.
Although the observed stereoselectivity does not allow
lepadin-type stereochemistries to be achieved, further
studies in aminocyclization processes, starting from
cyclohexenones of type 5, are in progress with the aim of
achieving the required stereochemistry of lepadin deriva-
tives. Interestingly, the reported methodology could be
applied to the synthesis of another type of natural
decahydroquinolines, such as trans-195A,28 5-epi-trans-
243A,29 and related alkaloids isolated from dendrobatid
frogs,27c which show the same pattern of relative
configuration as compounds 11a and 11b in their four
stereocenters.
3. Experimental
3.1. General
All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous
conditions. Analytical TLC was performed on SiO2 (silica
gel 60F254, Merck) or Al2O3 (ALOX N/UV254, Polygram),
and the spots were located with iodoplatinate reagent
(compounds 4, 5, 8, and 9) or 1% aqueous KMnO4
(compounds 6, 7, 10, and 11). Chromatography refers to
flash chromatography and was carried out on SiO2 (silica gel
60, SDS, 230–240 mesh ASTM) or Al2O3 (aluminium oxide
90, Merck). Drying of organic extracts during workup of
reactions was performed over anhydrous Na2SO4. Optical
rotations were recorded with a Perkin-Elmer 241 polari-
meter. 1H and 13C NMR spectra were recorded with a
Varian Gemini 200 or 300, or a Varian Mercury 400
instrument. Chemical shifts are reported in ppm downfield
(d) from Me4Si. All new compounds were determined to be
1
O95% pure by H NMR spectroscopy.
3.1.1. 2-[(2R,3S)-3-Dibenzylamino-2-hydroxybutyl]
cyclohex-2-enone ethylene acetal (4a). A solution of
6-bromo-1,4-dioxaspiro[4.5]dec-6-ene
(1,
1.04 g,
4.75 mmol) in THF (3 mL) was added to a solution of
n-BuLi (1.6 M in hexanes, 3.2 mL, 5.11 mmol) in THF
(7 mL) at K78 8C. The reaction mixture was stirred for
90 min, treated with a solution of (2S)-[10(S)-(dibenzyl-
amino)ethyl]oxirane (2a, 489 mg, 1.83 mmol) in THF
(6 mL) and BF3$Et2O (0.64 mL, 5.11 mmol), and continu-
ously stirred at K78 8C for 2 h prior to being quenched with
saturated NaHCO3 solution (10 mL) and warmed to rt. The

8268
M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270
product was extracted with Et2O (3!20 mL), the combined
organic layers were dried, concentrated, and the residue was
chromatographed (SiO2, elution with 9:1 hexane/EtOAc) to
give 560 mg (75%) of 4a as a colorless oil: RfZ0.31 (SiO2,
8:2 hexane/EtOAc); [a]2D0 C10.0 (c 1.2 in CHCl3); 1H NMR
(300 MHz, CDCl3) 1.15 (d, JZ6.3 Hz, 3H), 1.60–1.80 (m,
5H), 1.95–2.05 (br, 2H), 2.52–2.61 (m, 1H), 2.85 (dm, JZ
14 Hz, 1H), 3.25 (br, 1H), 3.45 (d, JZ13.8 Hz, 2H), 3.66–
3.73 (m, 1H), 3.77 (d, JZ13.8 Hz, 2H), 3.84–3.90 (m, 2H),
3.91–3.97 (m, 2H), 5.76 (t, JZ3 Hz, 1H), 7.18–7.40 (m,
10H); 13C NMR (50 MHz, CDCl3) 8.4 (CH3), 20.6 (CH2),
25.4 (CH2), 33.2 (CH2), 36.2 (CH2), 54.3 (CH2), 57.7 (CH),
64.6 (CH2), 64.7 (CH2), 74.1 (CH), 107.5 (C), 126.7 (CH),
128.1 (CH), 128.7 (CH), 133.6 (CH), 140.3 (C). HRFABMS
calcd for C26H34NO3 (MCC1) 408.2539, found 408.2516.
above, starting from 263 mg (0.64 mmol) of alcohol 4b,
and after chromatography (SiO2, 8:2 hexane/EtOAc),
acetate 5b (196 mg, 81%) was isolated as an oil: RfZ0.25
(SiO2, hexane/EtOAc, 8:2); [a]2D0 K32 (c 1.8 in CHCl3); 1H
NMR (300 MHz, CDCl3) 1.09 (d, JZ7.2 Hz, 3H), 1.86–
1.94 (m, 3H), 2.01 (s, 3H), 2.16–2.30 (m, 3H), 2.33–2.40
(m, 1H), 2.60 (dm, JZ14 Hz, 1H), 2.89 (quint, JZ7 Hz,
1H), 3.37 (d, JZ13.8 Hz, 2H), 3.87 (d, JZ13.8 Hz, 2H),
5.06 (ddd, JZ10.2, 6.2, 2.6 Hz, 1H), 6.60 (t, JZ4.2 Hz,
1H), 7.18–7.40 (m, 10H); 13C NMR (50 MHz, CDCl3): 9.7
(CH3), 21.2 (CH3), 22.9 (CH2), 26.1 (CH2), 33.0 (CH2), 38.2
(CH2), 54.3 (CH2), 55.4 (CH), 74.7 (CH), 126.6 (CH), 128.1
(CH), 128.8 (CH), 136.3 (C), 140.3 (C), 146.3 (CH), 170.3
(C), 198.8 (C). HRFABMS calcd for C26H32NO3 (MCC1)
406.2382, found 406.2339.
3.1.2. 2-[(2S,3S)-3-Dibenzylamino-2-hydroxybutyl]
cyclohex-2-enone ethylene acetal (4b). Operating as
above, starting from 881 mg (4.02 mmol) of 1 and using
(2R)-[10(S)-(dibenzylamino)ethyl]oxirane (2b, 414 mg,
1.55 mmol), and after chromatography (SiO2, 9:1 hexane/
EtOAc) 4b (518 mg, 82%) was isolated as an oil: RfZ0.28
3.1.5. Aminocyclization of 5a. A suspension of enone 5a
(50 mg, 0.12 mmol) and activated30 Pd(OH)2 in EtOH
(2 mL) was stirred overnight under hydrogen. The catalyst
was removed by filtration through Celite, and the solvent
was evaporated to give a residue, which was purified by
chromatography (Al2O3, 9:1 hexane/EtOAc) to give 6a
(13 mg, 54%) and 7a (9 mg, 36%), both as oils.
1
(SiO2, 9:1 hexane/EtOAc); H NMR (200 MHz, CDCl3)
1.05 (d, JZ6.6 Hz, 3H), 1.62–1.72 (m, 5H), 1.95–2.05 (br,
2H), 2.17–2.25 (m, 1H), 2.52–2.62 (m, 1H), 3.33 (d, JZ
13.6 Hz, 2H), 3.64–3.76 (m, 1H), 3.88 (d, JZ13.6 Hz, 2H),
3.90–3.98 (m, 4H), 5.93 (t, JZ2 Hz, 1H), 7.16–7.40 (m,
10H); 13C NMR (50 MHz, CDCl3) 8.6 (CH3), 20.6 (CH2),
25.3 (CH2), 33.6 (CH2), 34.3 (CH2), 53.6 (CH2), 58.2 (CH),
64.7 (CH2), 64.8 (CH2), 70.8 (CH), 107.8 (C), 127.0 (CH),
128.3 (CH), 128.9 (CH), 131.5 (CH), 139.2 (C).
(2S,3R,4aR,8aR)-3-Acetoxy-2-methyldecahydroquinoline
(6a). RfZ0.51 (Al2O3, 8:2 hexane/EtOAc); [a]2D0 K20.7 (c
1.3 in CHCl3); 1H NMR (400 MHz, CDCl3, COSY) 1.08 (d,
JZ6.4 Hz, 3H, Me), 1.20 (m, H-5ax), 1.40 (m, 3H, H-6ax
and H-7), 1.45 (m, H-4ax), 1.55 (m, H-8), 1.70 (m, H-8),
1.74 (m, 3H, H-4a, H-5eq, H-6eq), 1.87 (ddd, JZ11.0, 3.6,
1.2 Hz, H-4eq), 2.05 (s, 3H, OAc), 2.70 (dq, JZ10.0,
6.5 Hz, H-2ax), 2.95 (br s, H-8a), 4.58 (td, JZ10.5, 4.8 Hz,
H-3ax); 13C NMR see Table 1. HRFABMS calcd for
C12H22NO2 (MCC1) 212.1651, found 212.1646.
3.1.3. 2-[(2R,3S)-2-Acetoxy-3-(dibenzylamino)butyl]
cyclohex-2-enone (5a). To a solution of 4a (101 mg,
0.25 mmol) in pyridine (0.8 mL) and Ac2O (0.24 mL,
2.5 mmol) was added DMAP (5 mg, 0.04 mmol). The
reaction mixture was stirred overnight at rt. A saturated
NaHCO3 solution (15 mL) was added and the mixture was
extracted with CH2Cl2 (3!10 mL). The dried organic
extracts were concentrated to give the corresponding
acetate, which was used directly in the following acetal
hydrolysis step. The above crude acetal was dissolved in 1:1
H2O/THF (4 mL) and stirred at rt for 1 h. The reaction
mixture was basified with saturated aqueous NaHCO3
(15 mL) and extracted with CH2Cl2 (3!10 mL), and the
resulting organic extracts were dried and concentrated. The
residue was purified by chromatography (SiO2, hexane/
EtOAc 8:2) to give 5a as an oil (80 mg, 83%): RfZ0.27
(SiO2, 8:2 hexane/EtOAc); [a]2D0 C7.8 (c 0.7 in CHCl3); 1H
NMR (300 MHz, CDCl3) 1.08 (d, JZ6.6 Hz, 3H), 1.75–
1.83 (m, 1H), 1.83–1.93 (m, 2H), 1.94 (s, 3H), 2.16–2.28
(m, 2H), 2.31–2.38 (m, 2H), 2.75 (quint, JZ6 Hz, 1H), 3.18
(dm, JZ14 Hz, 1H), 3.41 (d, JZ13.6 Hz, 2H), 3.78 (d, JZ
13.6 Hz, 2H), 5.17 (ddd, JZ9.6, 7.6, 3.4 Hz, 1H), 6.53 (t,
JZ4 Hz, 1H), 7.17–7.41 (m, 10H); 13C NMR (50 MHz,
CDCl3) 8.8 (CH3), 21.2 (CH3), 22.9 (CH2), 26.2 (CH2), 33.2
(CH2), 38.2 (CH2), 53.9 (CH2), 55.1 (CH), 74.3 (CH), 126.7
(CH), 128.1 (CH), 129.0 (CH), 136.4 (C), 139.9 (C), 146.4
(CH), 170.4 (C), 198.7 (C). Anal. Calcd for C26H31NO3: C,
77.00; H, 7.70; N, 3.45. Found C, 76.75; H, 7.85; N, 3.39.
(2S,3R,4aS,8aR)-3-Acetoxy-2-methyldecahydroquinoline
1
(7a). H NMR (400 MHz, CDCl3, COSY) 1.02 (qd, JZ
10.4, 3.2 Hz, H-5ax), 1.10 (masked, H-4ax), 1.12 (d, JZ
6.4 Hz, 3H, Me), 1.20–1.30 (m, 2H, H-8ax and H-4a), 1.35
(m, 2H, H-6ax and H-7ax), 1.65 (m, 2H, H-7eq and H-5eq),
1.8 (m, 2H, H-8eq and H-6eq), 2.04 (s, 3H, OAc), 2.05
(masked, H-4eq), 2.19 (td, JZ10.4, 3.2 Hz, H-8a), 2.76 (dq,
JZ10, 6.4 Hz, H-2ax), 4.45 (td, JZ10.4, 4.4 Hz, H-3ax);
13C NMR see Table 1.
3.1.6. Aminocyclization of 5b. Operating as above, starting
from 49 mg (0.12 mmol) of enone 5b, and after chroma-
tography (Al2O3, from 9:1 to 7:3 hexane/EtOAc), 11 mg
(43%) of 6b and 11 mg (43%) of 7b, both as colorless oils,
were isolated.
(2S,3S,4aR,8aR)-3-Acetoxy-2-methyldecahydroquinoline
(6b). RfZ0.30 (Al2O3, 8:2 hexane/EtOAc); [a]2D0 C10.8 (c
0.8 in CHCl3); 1H NMR (400 MHz, CDCl3, COSY) 1.08 (d,
JZ6.6 Hz, 3H, Me), 1.20 (m, H-5ax), 1.40 (m, 3H, H-6ax,
H-7), 1.50 (m, 2H, H-8ax, H-4ax), 1.72 (m, 4H, H-4a,
H-5eq, H-6eq, H-8eq), 1.87 (ddd, JZ12, 3.6, 1.5 Hz,
H-4eq), 2.09 (s, 3H, OAc), 2.90 (qd, JZ6.8, 2 Hz, H-2ax),
2.92 (br, H-8a), 4.75 (ddd, JZ3.2, 3.2, 1.6 Hz, H-3eq); 13C
NMR see Table 1. HRFABMS calcd for C12H22NO2 (MCC
1) 212.1651, found 212.1648.
3.1.4. 2-[(2S,3S)-2-Acetoxy-3-(dibenzylamino)butyl]
cyclohex-2-enone ethylene acetal (5b). Operating as
(2S,3S,4aS,8aR)-3-Acetoxy-2-methyldecahydroquinoline

M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270
8269
(7b). RfZ0.23 (Al2O3, 8:2 hexane/EtOAc); [a]2D0 C28.6 (c
0.8 in CHCl3); H NMR (400 MHz, CDCl3, COSY) 0.94
JZ6.8 Hz, 3H), 1.11 (d, JZ6.4 Hz, 3H), 1.20–1.50 (m, 4H),
1.70–1.8 (m, 2H), 1.92 (s, 3H), 1.98–2.33 (m, 6H), 2.34–
2.42 (m, 1H), 2.71 (quint, JZ6.8 Hz, 1H), 3.08 (dd, JZ
13.6, 4.4 Hz, 1H), 3.45 (d, JZ13.6 Hz, 2H), 3.75 (d, JZ
13.6 Hz, 2H), 5.20 (ddd, JZ8.8, 6.8, 5.2 Hz, 1H), 7.18–7.40
(m, 10H); 13C NMR (50 MHz, CDCl3, HSQC) 8.9 (CH3),
14.1 (CH3), 21.2 (CH3), 22.4 (CH2), 22.9 (CH2), 28.3 (CH2),
30.1 (CH2), 30.8 (CH2), 34.7 (CH2), 37.7 (CH2), 54.0 (CH2),
55.2 (CH), 75.0 (CH), 126.7 (CH), 128.1 (CH), 128.9 (CH),
131.3 (C), 140.1 (C), 160.9 (C), 170.4 (C), 198.7 (C). Anal.
Calcd for C30H39NO3$H2O: C, 75.12; H, 8.62; N, 2.92.
Found C, 75.48; H, 9.02; N, 2.58.
1
(qd, JZ12, 3 Hz, H-5ax), 1.06 (dd, JZ6.8 Hz, 3H, Me),
1.21–1.34 (m, 5H, H-4ax, H-4a, H-6ax, H-7ax, H-8ax), 1.54
(dm, JZ12 Hz, H-5eq), 1.69 (dm, JZ12 Hz, H-6eq), 1.77
(dm, 2H, JZ12 Hz, H-7eq, H-8eq), 1.88 (dd, JZ10.8,
3.2 Hz, H-4eq), 2.12 (s, 3H, OAc), 2.22 (td, JZ10, 3.2 Hz,
H-8a), 2.92 (qd, JZ6.4, 1.6 Hz, H-2ax), 4.88 (ddd, JZ3.2,
3.2, 1.6 Hz, H-3eq); 13C NMR see Table 1. HRFABMS
calcd for C12H22NO2 (MCC1) 212.1651, found 212.1648.
3.1.7. 2-[(2R,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-1-
butylcyclohex-2-en-1-ol (8a). To a cooled (K78 8C)
solution of 5a (105 mg, 0.258 mmol) in THF (3 mL) was
added n-BuLi (1.6 M in hexanes, 0.8 mL, 1.29 mmol) and
the reaction mixture was stirred for 4 h, the temperature
slowly rising to rt. The reaction was quenched by addition of
saturated aqueous NH4Cl (20 mL) and extracted with
CH2Cl2 (3!20 mL). The dried organic extracts were
concentrated and the residue was dissolved in pyridine
(1 mL) and treated with Ac2O (0.25 mL, 2.58 mmol) and
DMAP (5 mg, 0.04 mmol). The reaction mixture was stirred
overnight at rt, saturated aqueous NaHCO3 (10 mL) was
added and the mixture was extracted with CH2Cl2 (3!
15 mL). The dried organic extract was concentrated and
purified by chromatography (SiO2, hexane/EtOAc 8:2) to
give the epimeric alcohols 8a and 1-epi-8a (81 mg, 68%), in
a 1:1 ratio according to the NMR spectrum, which were
used directly in the next step.Compound 8a. RfZ0.82 (SiO2,
3.1.10. 2-[(2S,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-3-
butylcyclohex-2-enone (9b). Operating as above, starting
from 71 mg (0.15 mmol) of alcohol 8b and after chroma-
tography (SiO2, 9:1 hexane/EtOAc), enone 9b (41 mg,
1
61%) was isolated as a viscous oil; H NMR (400 MHz,
CDCl3) 0.89 (t, JZ7.2 Hz, 3H), 1.10 (d, JZ6.8 Hz, 3H),
1.20–1.32 (m, 2H), 1.32–1.44 (m, 2H), 1.81–1.88 (m, 2H),
1.96 (s, 3H), 1.96–2.03 (m, 2H), 2.16–2.42 (m, 6H), 2.34–
2.42 (m, 1H), 2.68 (dd, JZ13.8, 11.0 Hz), 2.89–2.96 (m,
1H), 3.39 (d, JZ13.6 Hz), 3.90 (d, JZ13.6 Hz), 5.08 (ddd,
JZ11.0, 5.8, 2.4 Hz, 1H), 7.18–7.40 (m, 10H); 13C NMR
(50 MHz, CDCl3, HSQC) 9.7 (CH3), 14.1 (CH3), 21.1
(CH3), 22.4 (CH2), 23.0 (CH2), 28.4 (CH2), 30.1 (CH2), 30.9
(CH2), 34.8 (CH2), 37.8 (CH2), 54.5 (CH2), 55.8 (CH), 75.9
(CH), 126.7 (CH), 128.1 (CH), 128.7 (CH), 131.7 (C),
140.22 (C), 160.1 (C), 170.1 (C), 198.8 (C).
1
8:2 hexane/EtOAc); H NMR (200 MHz, CDCl3) 0.92 (t,
JZ6.8 Hz, 3H), 1.11 (d, JZ7.0 Hz, 3H), 1.18–1.38 (m, 4H),
1.49–1.80 (m, 7H), 1.82–1.93 (m, 2H), 1.98 (s, 3H), 2.75
(quint, JZ7 Hz, 1H), 2.95 (dm, JZ12 Hz, 1H), 3.44 (d, JZ
13.6 Hz, 2H), 3.75 (d, JZ13.6 Hz, 2H), 5.29–5.40 (m, 2H),
7.18–7.40 (m, 10H). Compound 1-epi-8a. RfZ0.64 (SiO2,
3.1.11. Aminocyclization of 9a. Following the above
procedure for the aminocyclization of 5a using enone 9a
(38 mg, 0.08 mmol) and carrying out the hydrogenation
process for 36 h, the crude product was purified by
chromatography (Al2O3, from 9:1 to 7:3 hexane/EtOAc)
to give 7 mg (33%) of 10a and 8 mg (38%) of 11a, both as
colorless oils.
1
8:2 hexane/EtOAc); H NMR (200 MHz, CDCl3) 0.89 (t,
JZ6.6 Hz, 3H), 1.06 (d, JZ6.6 Hz, 3H), 1.18–1.38 (m, 4H),
1.40–1.70 (m, 7H), 1.74–1.88 (m, 2H), 2.00 (s, 3H), 2.44–
2.54 (m, 1H), 2.85 (quint, JZ7 Hz, 1H), 3.48 (d, JZ
13.6 Hz, 2H), 3.73 (d, JZ13.6 Hz, 2H), 5.30 (m, 1H), 5.39
(t, JZ3.9 Hz, 1H), 7.18–7.40 (m, 10H).
(2S,3R,4aS,5R,8aR)-3-Acetoxy-5-butyl-2-methyldeca-
hydroquinoline (10a). RfZ0.59 (Al2O3, 8:2 hexane/
EtOAc); [a]2D0 K34.5 (c 0.5 in CHCl3); 1H NMR
(400 MHz, CDCl3, COSY) 0.90 (m, 1H, H-10), 0.90 (t,
JZ6.8 Hz, 3H, H-40), 1.10 (d, JZ6.4 Hz, 0 Me), 1.12
(masked, H-8ax), 1.20 (m, 4H, H-6 and H-2 ), 1.25 (m,
2H, H-30), 1.30 (m, H-4ax), 1.40 (m, H-4a), 1.48 (m, 2H,
H-7), 1.5 (m, H-8eq), 1.70 (m, 2H, H-5ax, H-10), 2.04 (s,
3H, OAc), 2.27 (ddd, JZ12.4, 3.6, 2.8 Hz, H-4eq), 2.76 (dq,
JZ10, 6.5 Hz, H-2ax), 2.97 (br s, H-8a), 4.49 (td, JZ10.4,
4.4 Hz, H-3ax); 13C NMR see Table 1. HRFABMS calcd for
C16H30NO2 (MCC1) 268.2198, found 268.2202.
3.1.8. 2-[(2S,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-1-
butylcyclohex-2-enol (8b). Operating as above, starting
from 147 mg (0.36 mmol) of cyclohexenone 5b, and after
chromatography (SiO2, hexane/EtOAc 8:2), 85 mg (51%) of
1
8b was obtained: RfZ0.58 (SiO2, 8:2 hexane/EtOAc); H
NMR (200 MHz, CDCl3) 0.91 (t, JZ6.8 Hz, 3H), 1.09 (d,
JZ7 Hz, 3H), 1.20–1.40 (m, 5H), 1.42–1.78 (m, 6H), 1.84–
1.96 (m, 2H), 2.05 (s, 3H), 2.18–2.28 (m, 1H), 2.85 (quint,
JZ7 Hz, 1H), 3.37 (d, JZ13.5 Hz, 2H), 3.90 (d, JZ
13.5 Hz, 2H), 5.13–5.22 (m, 1H), 5.45 (t, JZ3.7 Hz, 1H),
7.18–7.40 (m, 10H).
(2S,3R,4aR,5S,8aR)-3-Acetoxy-5-butyl-2-methyldeca-
hydroquinoline (11a). RfZ0.28 (Al2O3, 8:2 hexane/
EtOAc); [a]2D0 K4.3 (c 0.3 in CHCl3); 1H NM0R
(400 MHz, CDCl3, COSY) 0.88 (t, JZ6.8 Hz, 3H, H-4 ),
0.90 (masked, 1H, H-6ax), 0.94 (m, 2H, H-4ax, H-4a), 1.05
(masked, 2H, H-5 and H-10), 1.07 (d, 0JZ6.4 Hz, 3H, Me),
1.15 (m, 1H, H-8ax), 1.25 (m, 4H, H-2 , H-30), 1.30 (m, 1H,
H-7ax), 1.45 (m, 1H, H-10), 1.75 (m, 3H, H-6, H-7, H-8),
2.05 (s, 3H, OAc), 2.20 (ddd, JZ11, 9, 3 Hz, H-8a), 2.29
(dm, JZ12 Hz, H-4eq), 2.70 (dq, JZ10.4, 6.4 Hz, H-2ax),
4.41 (td, JZ10.4, 4.8 Hz, H-3ax); 13C NMR see Table 1.
3.1.9. 2-[(2R,3S)-2-Acetoxy-3-(dibenzylamino)butyl]-3-
butylcyclohex-2-enone (9a). To a solution of epimeric
alcohols 8a (81 mg, 0.18 mmol) in CH2Cl2 (2 mL) were
added PCC (57 mg, 0.26 mmol) and SiO2 (57 mg), and the
mixture was stirred overnight at rt. The residue obtained
after evaporation of the solvent was purified by chroma-
tography (SiO2, hexane/EtOAc 9:1) to give 9a as a viscous
oil (50 mg, 62%): RfZ0.36 (SiO2, 8:2 hexane/EtOAc); [a]D20
K5.3 (c 0.3 in CHCl3); 1H NMR (400 MHz, CDCl3) 0.91 (t,

8270
M. Mena, J. Bonjoch / Tetrahedron 61 (2005) 8264–8270
HRFABMS calcd for C16H30NO2 (MCC1) 268.2198,
found 268.2203.
(b) Yadav, V. K.; Senthil, G.; Babu, K. G.; Parvez, M.; Reis, J.
L. J. Org. Chem. 2002, 67, 1109–1117.
13. (a) Majetich, G.; Leigh, A. J.; Condon, S. Tetrahedron Lett.
1991, 32, 605–608. (b) Molander, G. A.; Bibeau, C. T.
Tetrahedron Lett. 2002, 43, 5385–5388.
¨
14. Scott, T. L.; Soderberg, B. C. G. Tetrahedron 2003, 59,
6323–6332.
15. (a) Lee, J.; Snyder, J. K. J. Org. Chem. 1990, 55, 4995–5008.
3.1.12. Aminocyclization of 9b. Operating as in the
cyclization of 9a, from enone 11 (22 mg, 0.05 mmol) was
obtained 11b as an oil (6 mg, 52%) after chromatography
(Al2O3, from 9:1 to 7:3 hexane/EtOAc).31
¨
(b) Scott, T. L.; Soderberg, B. C. G. Tetrahedron Lett. 2002,
43, 1621–1624.
(2S,3S,4aR,5S,8aR)-3-Acetoxy-5-butyl-2-methyldeca-
hydroquinoline (11b). RfZ0.13 (Al2O3, 8:2 hexane/
EtOAc); H NMR (400 MHz, CDCl3, COSY) 0.87 (t, JZ
1
16. Shih, C.; Fritzen, E. L.; Swenton, J. S. J. Org. Chem. 1980, 45,
4462–4471.
6.8 Hz, 3H, H0-4), 0.98 (m, 4H, H-4a, H-5, H-6, H-10), 1.06
(d, JZ6.8 Hz, 3H, Me), 1.15 (m, 2H, H-4ax, H-8ax), 1.25
(m, 4H, H-20 and H-30), 1.30 (m, H-7ax), 1.45 (m, 1H, H-10),
1.77 (m, 3H, H-8eq, H-7eq, H-6eq), 2.11 (s, 3H, OAc), 2.20
(dt, JZ10, 3.2 Hz, H-4eq), 2.27 (td, JZ10, 3 Hz, H-8a),
2.90 (qd, JZ6.4, 1.6 Hz, H-2ax), 4.91 (ddd, JZ3.2, 3.2,
1.6 Hz, H-3eq); 13C NMR see Table 1. HRFABMS calcd for
C16H30NO2 (MCC1) 268.2198, found 268.2194.
17. (a) Posner, G. H.; Frye, L. L.; Hulce, M. Tetrahedron 1984, 40,
1401–1407. (b) Mase, N.; Watanabe, Y.; Ueno, Y.; Toru, T. J.
Org. Chem. 1997, 62, 7794–7800.
18. (S)-Epoxide 2a has been described from N,N-dibenzylalaninal
19
by addition of sulfonium ylide CH2]SMe2 or a (halo-
methyl)lithium,20,21 but (R)-epoxide 2b has only been reported
20
by Barluenga and Concellon through addition of (chloro-
´
methyl)lithium upon the ethyl ester of N,N-dibenzylalanine
followed by diastereoselective reduction of the resulting a0-chloro
a-amino ketone and ring closure of the formed chlorohydrin.
19. Reetz, M. T.; Binder, J. Tetrahedron Lett. 1989, 30,
5425–5428.
Acknowledgements
This work was supported by the MEC, Spain (Project
CTQ2004-04701). Thanks are also due to the DURSI,
Catalonia, for Grant 2001SGR-00083. M. M. is a recipient
of a fellowship (MCYT, Spain).
´
20. Barluenga, J.; Baragan˜a, B.; Concellon, J.-M. J. Org. Chem.
1995, 60, 6696–6699.
21. Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635–3645.
22. For a recent study on the reactivity of epoxides 2, see:
´ ´ ´ ´
Concellon, J. M.; Suarez, J. R.; Garcıa-Granda, S.; Dıaz, M.-R.
Org. Lett. 2005, 7, 247–250.
23. Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984,
106, 3693–3694.
References and notes
24. Ring opening of epoxides catalyzed by BF3$Et2O:
Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky,
D. J. J. Org. Chem. 1991, 56, 5161–5169. For the generation of
oxiranyl anions and further olefin formation with alkylation by
reaction of epoxides with alkyllithiums, see: Satoh, T. Chem.
Rev. 1996, 96, 3303–3325.
1. Lepadin, A.; Steffan, B. Tetrahedron 1991, 47, 8729–8732.
2. Lepadins, B.-C.; Kubanek, J.; Williams, D. E.; de Silva, E. D.;
Allen, T.; Anderson, R. J. TetrahedronLett. 1995, 36, 6189–6192.
¨
3. Lepadins, D.-F.; Wright, A. D.; Goclik, E.; Konig, G. M.;
Kaminsky, R. J. Med. Chem. 2002, 45, 3067–3072.
4. Lepadins, F.-H.; Davis, R. A.; Carroll, A. R.; Quinn, R. J. J.
Nat. Prod. 2002, 65, 454–457.
25. Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682–685.
26. (a) McKenzie, T. C. J. Org. Chem. 1974, 39, 629–631. (b)
Overman, L. E.; Tomasi, A. L. J. Am. Chem. Soc. 1998, 120,
4039–4040.
5. (a) Toyooka, N.; Okumura, M.; Takahatam, H. J. Org. Chem.
1999, 64, 2182–2183. (b) Toyooka, N.; Okumura, M.;
Takahatam, H.; Nemoto, H. Tetrahedron 1999, 55,
10673–10684.
27. For NMR studies of decahydroquinolines, see: (a) Eliel, E. L.;
Vierhapper, F. W. J. Org. Chem. 1976, 41, 199–208. b
Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1977, 42, 51–62.
(c) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh,
H. J. C.; Daly, J. W.; Fukumoto, S.; Imamura, K.; Torres, J. A.;
Snelling, R. R.; Jones, T. H. J. Nat. Prod. 1999, 62, 5–21.
6. (a) Osawa, T.; Aoyagi, S.; Kobayashi, C. Org. Lett. 2000, 2,
2955–2958. (b) Osawa, T.; Aoyagi, S.; Kobayashi, C. J. Org.
Chem. 2001, 66, 3338–3347.
7. Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222–4225.
8. Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun. 2002,
1430–1431.
¨
28. Holub, N.; Neidhofer, J.; Blechert, S. Org. Lett. 2005, 7,
1227–1229.
9. Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro, M. A. J.
Org. Chem. 1982, 47, 1855–1869.
29. Tokuyama, T.; Tsujita, T.; Shimada, A.; Garraffo, H. M.;
Spande, T. F.; Daly, J. W. Tetrahedron 1991, 47, 5401–5414.
30. Yoshida, K.; Nakajima, S.; Wakamatsu, T.; Ban, Y.;
Shibasaki, M. Heterocycles 1988, 27, 1167–1170.
10. (a) Tokoroyama, T.; Tsukamoto, M.; Iio, H. Tetrahedron Lett.
1984, 25, 5067–5070. (b) Baldwin, J. E.; Adlington, R. M.;
Robertson, J. Tetrahedron 1989, 45, 909–922. (c) Laschat, S.;
Narjes, F.; Overman, L. E. Tetrahedron 1994, 50, 347–358. (d)
Sha, C.-K.; Ouyang, S.-L.; Hsieh, D.-Y.; Chang, R.-C.; Chang,
S.-C. J. Org. Chem. 1986, 51, 1490–1494. (e) Anderson, J. C.;
Pearson, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2023–2029.
11. (a) Paquette, L. A.; Su, Z.; Bailey, S.; Montgomery, F. J. J.
Org. Chem. 1995, 60, 897–902. (b) Warrington, J. M.; Yap, G.
P. A.; Barriault, L. Org. Lett. 2000, 2, 663–665.
31. Minor signals (approximately in a 1:3 ratio with respect to the
major compound isolated 11b) in the NMR of the crude
reaction mixture at d 4.76 (ddd, JZ3.2, 3.2, 1.6 Hz, H-3eq),
2.96 (m, H-8a), 2.66 (qd, JZ6.4, 3.2 Hz, H-2ax), and 2.16
(dm, JZ12 Hz, H-4eq) were observed. They could be
attributed to the isomer 10b, which cannot be isolated in
pure form. The isolated decahydroquinoline 11b remains
partially contaminated by this compound even after repeating
the chromatography.
12. (a) Bodwell, G. J.; Pi, Z. Tetrahedron Lett. 1997, 38, 309–312.