Synthesis of enantiopure cis-decahydroquinolines from homotyramines by Birch reduction and aminocyclization

Article abstract of DOI:10.1016/j.tet.2006.07.035

Birch reduction of homotyramines with a syn-β-amino alcohol unit followed by acid treatment of formed dihydroanisole derivatives gives polysubstituted enantiopure cis-decahydroquinolines. The stereoselectivity of the process differs if the hydroxyl group

Full text of DOI:10.1016/j.tet.2006.07.035

Tetrahedron 62 (2006) 9166–9173
Synthesis of enantiopure cis-decahydroquinolines from
homotyramines by Birch reduction and aminocyclization
*
ꢀ
Marisa Mena, Nativitat Valls, Mar Borregan and Josep Bonjoch
´
Laboratori de Quımica Organica, Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain
ꢁ
ꢁ
Received 20 June 2006; accepted 11 July 2006
Available online 4 August 2006
Abstract—Birch reduction of homotyramines with a syn-b-amino alcohol unit followed by acid treatment of formed dihydroanisole deriv-
atives gives polysubstituted enantiopure cis-decahydroquinolines. The stereoselectivity of the process differs if the hydroxyl group is free
or protected. The procedure allows the synthesis of 7-oxodecahydroquinolines embodying four stereogenic centres with the same relative
configuration as that of lepadins F and G.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
which has a methyl group at C(2), a hydroxyl group, free or
protected, at C(3) and a functionalized side chain at C(5),
shows a variety of stereochemical arrangements.8 Total
enantioselective syntheses of lepadins A,9 B,9–11 C,9 D–E11
and H,11 as well as a formal route to rac-lepadin B12 have
been reported.
The use of (u-aminoalkyl)methoxybenzene derivatives
(e.g., tyrosine and tyramine compounds) as starting mate-
rials to elaborate azabicyclic compounds through a Birch
reduction followed by an intramolecular cyclization of the
resulting amino-tethered cyclohexenone (Scheme 1) is well-
precedented in the literature. Following this methodology,
octahydroindoles,1,2 azaspiroundecanes,3 6-azabicyclo-
[3.2.1]octanes,4 2-azabicyclo[3.3.1]nonanes,5 and deca-
hydroquinolines6 have been prepared, but, apart from of
our work on the synthesis of enantiopure octahydroindoles,2
all described processes lead to racemic compounds.
We focused our attention on the synthesis of cis-decahydro-
quinolines incorporating a methyl at C(2) and a hydroxyl at
C(3), with an S configuration at both stereogenic centres, as
occurs in lepadins A, B and C. In lepadins F and G both sub-
stituents also have a cis relationship, although their absolute
configuration is unknown (see Scheme 2). The strategies
described for the construction of 3-hydroxy-2-methyldeca-
hydroquinolines involve the elaboration of a polyfunctional-
ized piperidine followed by carbocyclic ring closure through
aldol processes9,10 or the construction of the piperidine ring
from cyclohexanone derivatives either by an intramolecular
enamine alkylation11 or by using a xanthate-mediated radi-
cal cyclization.12 In our approach, we envisaged enantiopure
anisole derivatives of type I (R¼H or Me) as potential inter-
mediates for the aforementioned cis-decahydroquinolines,
as they would bring about ring closure by forming the
N–C(8a) bond.13
n
n
n
NH2
NH2
N
O
MeO
O
Scheme 1. The Birch reduction/aminocyclization process leading to azabi-
cyclic compounds.
In this paper, we describe the synthesis of enantiopure poly-
substituted decahydroquinolines from homotyramine pre-
cursors following the aforementioned Birch reduction/
aminocyclization sequence.7 The interest of this work, aside
from studying the stereocontrol of the process, lies in the
possible usefulness of the resulting compounds in the syn-
thesis of lepadin alkaloids. These natural products are struc-
turally characterized by the presence of a 2,3,5-trisubstituted
cis-fused decahydroquinoline ring. The substitution pattern,
2. Results and discussion
2.1. Synthetic aspects
For the proposed studies of Birch reduction of homotyr-
amines followed by an aminocyclization process to achieve
cis-decahydroquinolines of interest in the lepadin field,
a-methyl-b-aminoalcohol I was required. The synthesis
of syn-a-methyl-b-amino alcohols (II, Scheme 3) is
Keywords: Lepadin alkaloids; Decahydroquinolines; Epoxides; Conforma-
tional analysis; Nitrogen heterocycles.
* Corresponding author. Tel.: +34 934024540; fax: +34 934024539; e-mail:
josep.bonjoch@ub.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.035

M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
9167
Scheme 2. Retrosynthetic approach to lepadin alkaloids.
well-precedented not only by the methodological studies of
the reactivity of alanine derivatives but also by the presence
of this structural motif in several natural products other than
the aforementioned lepadins, such as various piperidine
alkaloids14 (i.e., carpamic acid, azimic acid, julifloridine
and cassine inter alia). The most suitable procedures for
syn amino alcohols of type II are the organometallic addition
upon the Weinreb amide of N,N-dibenzylalanine15 followed
by hydride reduction of the resulting a-amino ketone16 or the
organometallic addition upon the N-Boc-alaninal.17,18 To our
knowledge, none of these versatile approaches have been
used in reactions involving p-methoxybenzylmagnesium
bromide, as was required in the present work. We decided
to use the protocol involving the Weinreb amide of N,N-di-
benzylalanine and, in addition, introduced a new approach
based on the ring-opening of a suitable epoxidewith a lithium
reagent is introduced to achieve aminoalcohol I.
MgBr
+
Me
N
O
O
OMe
(87%)
MeO
Bn
Me
N
Bn
MeO
Me
NBn2
2
1
NaBH4 (90%)*
OH
O
Li
(69%)
MeO
+
Bn
Me
N
Bn
MeO
Me
NBn2
3
4a
OH
Me
OH
H2, Pd(OH)2
MeO
Li, NH3,
EtOH
Me
MeO
NH2
NH2
6a
5a
Me
N
OH
Me
O
R
H
OMe
H
CHO
Me
OH
Me
OH
aq HCl
+
Me
Bn
H
R'
N
Bn
N
N
PG
Me
N
N
H
O
O
Boc
H
H
H
II
7a
(43% from 4a)
Scheme 4. Synthesis of cis-decahydroquinolines.
8a
(I, when R = 4-OMeC6H4CH2;
R' = PG = H)
(17% from 4a)
Scheme 3. Synthesis of enantiopure syn-a-methyl-b-amino alcohols.
Coupling of either the p-methoxybenzylmagnesium bromide
with Weinreb amide 119,20 or the p-methoxyphenyllithium
with the (R) isomer of [(S)-10-(dibenzylamino)ethyl]oxirane
(3)21 in the presence of BF3$Et2O (Ganem’s conditions)22,23
gave synthetic access to the required aminoalcohol 4a, a dia-
stereoselective reduction of the initially formed b-amino
ketone 2 being necessary in the former sequence (Scheme 4,
* denotes that 10% of the epimer of 4a24 was additionally
isolated in this route, see Section 3). A loss of enantiopurity
observed in this sequence (1/4a) when the coupling of the
Weinreb amide 1 was carried out at 0 ꢀC25 and was avoided at
ꢁ40 ꢀC.
bond isomerization and an intramolecular 1,4-addition of
the amino group across the cyclohexenone intermediate.
The process is stereoselective, with the exclusive formation
of cis-isomers of the decahydroquinoline ring. Polysubsti-
tuted decahydroquinolines 7a (43%) and 8a (17%) were
isolated in a 2.5:1 ratio and a overall yield of 60% from
the sequence 4a/7a+8a.
We then carried out the same sequence of reactions but start-
ing from syn-amino ether 4b, which was obtained by O-
methylation of aminoalcohol 4a (Scheme 5). In this series,
the aminocyclization step starting from dihydroanisole 6b
gave a 1:2.3 mixture of decahydroquinolines 7b and 8b,
which were only partially separated. However, when the
reaction mixture was basified and treated with benzoyl
chloride after aminocyclization, the corresponding amides
9b and 10b were isolated in 17 and 39% overall yields
(four steps from 4b).
Debenzylation of 4a gave the primary amine 5a, which was
submitted to the Birch reduction conditions (Li/NH3) to al-
low the formation of dihydroanisole 6a. This was treated
with a 2 N HCl solution at 75 ꢀC, and the decahydroquino-
line ring was formed after enol ether hydrolysis, double

9168
M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
Me
C-4a and C-8a) is controlled to some extent by the oxygen-
ii) H2,
ated function. Why does the decalin ring formation change
diastereoselectivity if there is a free or protected hydroxyl
group? Considering that the axial attack proceeds through
a chair-like transition state in the hydroxyl series perhaps
a hydrogen bonding favours the formation of enone A with
respect to the epimeric enone A0, which could be in equilib-
rium by means of a tautomeric process through their corre-
sponding dienol ether. On the contrary in series b, in
which the hydroxyl group is protected as methyl ether, the
steric factors (a 1,3-diaxial relationship between the C3–
OMe and C4a–C5 bonds) prevent to some extent the forma-
tion of epimer B, and the formation of B0 being favoured
(Scheme 6). Thus, the ratio of cis-decahydroquinoline with
an S configuration at the two new stereogenic centres formed
in the aminocyclization to the diastereoisomers with a R con-
figuration was higher in compounds with a methoxy rather
than hydroxyl substituent.
i) MeI, NaH
(90%)
N(Bn)2
4a
Pd(OH)2
OMe
MeO
4b
OMe
Me
iii) Li, NH3,
EtOH
iv) HCl
5b
MeO
NH2
6b
H
H
H
OMe
Me
OMe
Me
+
N
H
O
N
H
O
H
7b
8b
H
H
H
OMe
OMe
v) BzCl,
K2CO3
2.2. NMR studies of decahydroquinolines 7–10
(series a and b)
+
Me
COC6H5
10b
Me
N
N
O
O
H
COC6H5
The stereochemistry of the synthesized azabicyclic com-
pounds was elucidated by 2D NMR spectra (COSY, HSQC).
The N-inside (7a and 7b) and N-outside (8a and 8b) cis-
decahydroquinoline isomers26 in the amino series are clearly
differentiated by two NMR features: (i) the 1H NMR chem-
ical shift of H-2, which appears more deshielded (d 3.1) in
the N-outside than in the N-inside derivatives (d 2.8), due
to the compression upon H-2 of the C8–C8a bond, which
has a 1,3-cis relationship, on the N-outside derivatives; (ii)
the 13C NMR chemical shift of C(2) is more upfielded
(w10 ppm) in compounds with the N-outside conformation
than those with the N-inside conformation; moreover the
signals given by the carbon atoms at C-4, C-6 and C-8 also
appear in a higher field in the N-outside derivatives.
9b
(17% from 4b)
(39% from 4b)
Scheme 5.
In the cyclization processes (6/7+8), both in series a (3-
OH) and series b (3-OMe), the isolated decahydroquinolines
showed a cis-fused relationship. The major compound of
series a (i.e., 7a) showed the same pattern of absolute config-
uration in its four stereocentres as lepadins A–C, while that
of series b (i.e., 8b) matched the relative configuration of
lepadins F and G, allowing them to be considered as ad-
vanced building blocks for elaborating the aforementioned
alkaloids.
The key evidence for the conformational elucidation of 7a
was found in the 1H NMR coupling pattern for the methylene
protons at C-8, which appear as dd (J¼14.6, 5.4 Hz). The
relative configuration for methoxy derivative 7b is the
same as that observed in 7a and their NMR data follows
the same pattern of chemical shifts (Scheme 2). The absolute
configuration of 7a was deduced by considering that: (a) the
The stereoselectivecis-perhydroquinolineformationthrough
a 6-exo process agreed with the stereochemical outcome ob-
served in related cyclizations,6 and with both the steric and
electronic preferences for a pseudo axial addition of the
nucleophilic species to the cyclohexenone moiety. Interest-
ingly, the configuration of the new methine carbons (i.e.,
H
O
Me
H
O
Me
H
H
H
NH2
OMe
NH2
OH
OMe
H
OH
H
vs
vs
H
NH2
H
NH2
Me
Me
O
A
A'
B'
O
B
O
H
O
H
H
H
Me
H
H
H
H
N
OMe
H
H
OH
H
N
H
H
H
H
N
conformational
change
H
Me
7a
Me
OMe
H
O
8b
Scheme 6.

M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
9169
coupling constants for H-2 (qd, J¼6.6, 2 Hz) and H-3 (q,
J¼2.4 Hz) determined their location and hence fixed the
methyl at C(2) and the hydroxyl at C(3) to an equatorial
and axial disposition, respectively; (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 a R configuration for
C(8a). For the major component in the methoxy series 8b,
the axial proton H-8a is strongly coupled to one adjacent
axial. Hence, its resonance signal appears as a deceptively
simple doublet (J¼10.4 Hz) of triplets (J¼4.8 Hz) centred
at d 3.43.
progress with the aim of achieving lepadins A–C and F and
G, respectively.
3. Experimental
3.1. General
All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous condi-
tions. Analytical TLC was performed on SiO2 (silica gel 60
F254, Merck) or Al2O3 (ALOX N/UV254, Polygram), and
the spots were located with iodoplatinate reagent (com-
pounds 1–8) or 1% aqueous KMnO4 (compounds 9 and
10). 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 or-
ganicextractsduringworkupofreactionswasperformedover
anhydrous Na2SO4. Optical rotations were recorded with
In summary, the twin chair conformation with the nitrogen
axially substituting the carbocyclic ring is the lowest energy
conformation for 7a, whereas the twin chair conformation
with the nitrogen equatorially substituting the carbocyclic
ring is the lowest energy conformation for 8b (Fig. 1).
1
a Perkin–Elmer 241 polarimeter. H and 13C NMR spectra
were recorded with a Varian Gemini 200 or 300, or a Varian
Mercury 400 instrument. Chemical shifts are reported in parts
per million downfield (d) from Me4Si. All new compounds
were determined to be >95% pure by 1H NMR spectroscopy.
Interestingly, the N-benzoyl derivatives 9a, prepared from
amine 7a in quantitative yield, and 10b (Fig. 2) showed a dif-
ferent preferred conformations to that of their precursors 7a
and 8b, respectively, as has been observed in synthetic inter-
mediates in lepadin synthesis9–11 when the amino group is
converted to a carbamate or amide group.
3.1.1. (S)-(N,N-Dibenzyl)amino-N-methoxy-N-methyl-
propionamide (1). To a solution of benzyl (S)-2-(N,N-
dibenzylamino)propionate27
HCl$HN(OMe)Me (3.0 g, 30 mmol) in THF (90 mL) at
(2.15 g,
6 mmol)
and
In summary, a new synthetic entry to enantiopure polysubsti-
tuted cis-decahydroquinolines has been reported. Since the
observed stereoselectivity allows lepadin-type stereochem-
istries to be achieved, further studies using decahydroquino-
lines 9a and 10b as advanced synthetic intermediates are in
i
ꢁ20 ꢀC, PrMgCl (30 mL of a 2 M in THF, 60 mmol) was
added dropwise over a period of 30 min. The reaction mix-
ture was stirred for 2 h at this temperature and then warmed
to rt for 2.5 h. NH4Cl (20 mL) was added and the product
was extracted with CH2Cl2 (3ꢂ20 mL). The combined
organic layer was dried and concentrated to an oil, which
contained 1 and BnOH. The latter was removed under vac-
uum to afford compound 1 (1.94 g), which was used without
further purification. The 1H NMR data were identical to those
previously reported.20 Rf ¼0.1 (SiO2, 9:1 hexane/EtOAc);
13C NMR (50 MHz, CDCl3) 14.9 (CH3), 54.4 (CH2), 56.1
(CH), 60.1 (CH2), 126.8 (CH), 127.4 (CH), 127.6 (CH),
128.1 (CH), 128.3 (CH), 128.5 (CH), 139.8 (C), 173.9 (C).
O
H
H
H
H
Me
H
H
H
H
N
HO
H
H
H
H
N
Me
OH
H
O
7a
8a
O
H
H
3.1.2. (3S)-3-(N,N-Dibenzyl)amino-1-(4-methoxyphe-
nyl)butan-2-one (2). To a solution of 1 (1.81 g, 5.8 mmol)
in THF (50 mL) at ꢁ40 ꢀC, 2-methoxybenzylmagnesium
chloride 0.25 M in THF (46 mL, 11.6 mmol) was added
dropwise. The reaction mixture was stirred for 2 h 30 min
at ꢁ40 ꢀC and then quenched with NH4Cl. The organic layer
was dried and concentrated to an oil, which was purified by
chromatography (SiO2, 9:1 hexane/EtOAc) to give 2 as a col-
ourless oil (2.17 g, 87%). Rf ¼0.5 (SiO2, 9:1 hexane/EtOAc);
H
H
H
Me
H
H
H
H
N
MeO
H
H
H
N
Me
H
OMe
O
7b
8b
N-inside conformation
N-outside conformation
Figure 1. Preferred conformation of decahydroquinolines 7 and 8.
1
[a]2D5 ꢁ8.8 (c 1.0, CHCl3); IR (KBr) 1715, 1611 cmꢁ1; H
NMR (300 MHz, CDCl3) 1.15 (d, J¼6.6 Hz, 3H), 3.47 (d,
J¼13.2 Hz, 2H), 3.52 (q, J¼6.6 Hz, 1H), 3.72 (d,
J¼15.0 Hz, 1H), 3.74 (d, J¼13.2 Hz, 2H), 3.76 (s, 3H),
3.88 (d, J¼15.3 Hz, 1H), 6.74 (d, J¼8.6 Hz, 2H), 6.84 (d,
J¼8.6 Hz, 2H), 7.20–7.40 (m, 10H); 13C NMR (75 MHz,
CDCl3) 7.1 (CH3), 45.3 (CH2), 54.6 (CH2), 55.2 (CH3),
60.6 (CH), 113.8 (CH), 126.5 (C), 127.2 (CH), 128.4
(CH), 128.9 (CH), 130.3 (CH), 139.2 (C), 158.3 (C). Anal.
Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found:
80.00; H, 7.29; N, 3.67.
H
H
O
H
OH
H
N
H
OMe
H
N
Bz
H
Me
Bz
H
H
Me
O
9a
10b
Figure 2. Preferred conformation of decahydroquinolines 9 and 10.

9170
M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
3.1.3. (2S,3S)-3-(N,N-Dibenzyl)amino-1-(4-methoxyphe-
nyl)butan-2-ol (4a). Method A (from ketone 2): to a solution
of 2 (2.15 g, 5.75 mmol) in MeOH (68 mL) at ꢁ20 ꢀC,
NaBH4 (453 mg, 11.5 mmol) was added. The reaction mix-
ture was stirred for 1 h at this temperature, and then
quenched with brine (30 mL). The product was extracted
with CH2Cl2 (3ꢂ30 mL), dried and concentrated to give
a mixture of alcohols 4a and epi-4a24 in a 9:1 ratio according
to the NMR spectrum. Purification by chromatography
(SiO2, 9:1 hexane/EtOAc) gave 4a (1.94 g, 90%) and epi-
4a (216 mg, 10%).
give an oil, which was purified by chromatography (SiO2,
9:1 hexane/EtOAc) to give 4b as a colourless oil (1.14 g,
90%). Rf ¼0.42 (SiO2, 9:1 hexane/EtOAc); [a]2D5 ꢁ4.6 (c
1
1.0, CHCl3); IR (KBr) 1611 cmꢁ1; H NMR (300 MHz,
CDCl3) 1.13 (d, J¼6.9 Hz, 3H), 2.74–2.88 (m, 3H), 3.13
(s, 3H), 3.22 (dt, J¼7.2, 4.8 Hz, 1H), 3.43 (d, J¼13.5 Hz,
2H), 3.77 (s, 3H), 4.01 (d, J¼13.5 Hz, 2H), 6.73 (d,
J¼8.7 Hz, 2H), 6.94 (d, J¼8.7 Hz, 2H), 7.20–7.32 (m,
6H), 7.39–7.41 (m, 4H); 13C NMR (75 MHz, CDCl3) 10.1
(CH3), 37.4 (CH2), 55.1 (CH), 55.2 (CH2), 55.2 (CH3),
59.2 (CH3), 88.1 (CH), 113.5 (CH), 126.6 (CH), 128.1
(CH), 128.9 (CH), 130.2 (CH), 132.3 (C), 140.9 (C), 157.7
(C). Anal. Calcd for C26H31NO2: C, 80.17; H, 8.02; N,
3.60. Found: C, 80.07; H, 8.31; N, 3.40.
Compound 4a: colourless oil. Rf ¼0.24 (SiO2, 9:1 hexane/
EtOAc); [a]2D5 ꢁ5.6 (c 1.4, CHCl3); IR (KBr) 3600–3100,
1611 cmꢁ1
;
1H NMR (300 MHz, CDCl3) 1.07 (d,
J¼6.6 Hz, 3H), 2.38 (dd, J¼14.0, 7.8 Hz, 1H), 2.60 (dq,
J¼9.3, 6.6 Hz, 1H), 2.78 (dd, J1¼14.3, 3.0 Hz, 1H), 3.30
(d, J¼13.5 Hz, 2H), 3.68 (m, 1H), 3.77 (s, 3H), 3.82 (d,
J¼13.5 Hz, 2H), 6.77 (d, J¼9 Hz, 2H), 7.11 (d, J¼9 Hz,
2H), 7.20–7.40 (m, 10H); 13C NMR (75 MHz, CDCl3) 8.3
(CH3), 39.1 (CH2), 53.2 (CH2), 55.2 (CH3), 57.7 (CH),
71.9 (CH), 113.5 (CH), 127.1 (CH), 128.4 (CH), 128.9
(CH), 130.1 (CH), 131.0 (C), 138.7 (C), 157.8 (C). Anal.
Calcd for C25H29NO2$1/2H2O: C, 78.12; H, 7.81; N, 3.64.
Found: C, 77.84; H, 8.16; N, 3.34.
3.1.5. (2S,3S)-3-Amino-1-(4-methoxyphenyl)butan-2-ol
(5a). A suspension of 4a (2.16 g, 5.75 mmol) and
Pd(OH)2/C (210 mg, 20%) in EtOH (110 mL) was stirred
at rt under hydrogen atmosphere overnight. The catalyst
was removed by filtration through Celite and the filtrate
was concentrated to give 5a as an oil (1.12 g), which was
used directly in the next step. An analytical sample was ob-
tained by chromatography (Al2O3, CH2Cl2 saturated with
1
NH3). [a]2D5 ꢁ15.5 (c 0.7, CHCl3); H NMR (300 MHz,
CDCl3) 1.12 (d, J¼6.6 Hz, 3H), 2.56 (dd, J¼14.0, 8.6 Hz,
1H), 2.74–2.86 (m, 2H), 3.40–3.46 (m, 1H), 3.78 (s, 3H),
6.84 (d, J¼8.7 Hz, 2H), 7.14 (d, J¼8.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3) 20.5 (CH3), 39.6 (CH2), 50.3 (CH), 54.7
(CH2), 55.2 (CH3), 76.4 (CH), 113.7 (CH), 130.1 (C),
130.2 (CH), 158.0 (C).
Compound epi-4a: colourless oil. Rf ¼0.14 (SiO2, 9:1 hex-
1
ane/EtOAc); IR (KBr) 3600–3100, 1611 cmꢁ1; H NMR
(300 MHz, CDCl3) 1.17 (d, J¼6.6 Hz, 3H), 2.30 (dd,
J¼13.8, 9.6 Hz, 1H), 2.75 (quint, J¼6.9 Hz, 1H), 3.21 (dd,
J¼13.8, 3.0 Hz, 1H), 3.50 (J¼13.8 Hz, 2H), 3.73–3.81 (m,
1H), 3.80 (d, J¼14.1 Hz, 2H), 6.80 (d, J¼9.0 Hz, 2H),
7.02 (d, J¼9.0 Hz, 2H), 7.20–7.40 (m, 10H); 13C NMR
(75 MHz, CDCl3) 8.6 (CH3), 40.6 (CH2), 54.7 (CH2), 55.3
(CH3), 57.2 (CH), 74.7 (CH), 113.9 (CH), 126.8 (CH),
128.2 (CH), 128.8 (CH), 130.2 (CH), 131.0 (C), 140.0 (C),
158.1 (C).
3.1.6. (2S,3S)-3-Methoxy-4-(4-methoxyphenyl)-2-butan-
amine (5b). Operating as above, starting from 4b (1.14 g,
2.92 mmol), 5b was obtained (615 mg) as an oil, which
was used directly in the next step. An analytical sample
was obtained by chromatography (Al2O3, 98:2 CH2Cl2 satu-
rated with NH3/MeOH). [a]2D5 +8.4 (c 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3) 1.11 (d, J¼6.3 Hz, 3H), 2.56 (dd,
J¼14.3, 6.5 Hz, 1H), 2.90–2.81 (m, 2H), 3.07 (dt, J¼6.6,
5.4 Hz, 1H), 3.30 (s, 3H), 3.79 (s, 3H), 6.84 (d, J¼8.4 Hz,
2H), 7.15 (d, J¼8.4 Hz, 2H); 13C NMR (50 MHz, CDCl3)
20.1 (CH3), 35.8 (CH2), 49.2 (CH), 55.2 (CH3), 58.8
(CH3), 87.6 (CH), 113.7 (CH), 130.4 (CH), 130.8 (C),
158.0 (C).
Method B (from epoxide 3): to a solution of n-BuLi (1.6 M in
hexanes, 1.05 mL, 1.68 mmol) in THF (3.5 mL) at ꢁ78 ꢀC
was added 4-bromoanisole (0.2 mL, 1.56 mmol). The
reaction mixture was stirred for 90 min, treated with a solu-
tion of (2R)-[10(S)-(dibenzylamino)ethyl]oxirane21 (162 mg,
0.6 mmol) in THF (2 mL) and BF3$Et2O (0.21 mL,
1.68 mmol) and continuously stirred at ꢁ78 ꢀC for 2 h prior
to being quenched with saturated NH4Cl (4 mL) and warmed
to rt. The product was extracted with CH2Cl2 (3ꢂ10 mL),
and the organic layer was dried and concentrated to give
an oil, which was purified by chromatography (SiO2, 9:1
hexane/EtOAc) to give 4a as a colourless oil (153 mg,
69%). The spectroscopic data and specific rotation were
identical with the product obtained by method A.
3.1.7. (2S,3S)-3-Amino-1-(4-methoxy-2,5-dihydrophe-
nyl)butan-2-ol (6a). To
a solution of 5a (1.12 g,
5.75 mmol) in EtOH (6 mL) at ꢁ78 ꢀC, ammonia (46 mL)
was added. Small chips of lithium (280 mg, 40 mmol)
were added until the solution become a persistent deep
blue for 1.5 h. The cooling bath was removed, the ammonia
was allowed to evaporate overnight and the reaction mixture
was evaporated. The dried extract was dissolved in brine
(15 mL) and the product was extracted with CH2Cl2
(3ꢂ15 mL), dried with Na2SO4 and concentrated to give
6a (1.112 g) as an oil, which was used directly in the next
3.1.4. (2S,3S)-N,N-Dibenzyl-3-methoxy-4-(4-methoxy-
phenyl)-2-butanamine (4b). To a suspension of NaH
(195 mg, 4.89 mmol) in THF (2 mL) at 0 ꢀC a solution of
4a (1.22 g, 3.26 mmol) in THF was transferred
(1 mL+1 mL). The reaction mixture was warmed over
20 min to rt and then MeI (2 mL, 32.6 mmol) was added.
The reaction was sealed and stirred for 48 h. NH4Cl was
added (10 mL) and the product was extracted with CH2Cl2
(3ꢂ20 mL). The resulting organic layer was washed with
H2O (15 mL) and brine (15 mL), dried and concentrated to
1
step. H NMR (200 MHz, CDCl3) 1.11 (d, J¼6.3 Hz, 3H),
2.08 (dd, J¼14.1, 9.0 Hz, 1H), 2.21 (dd, J¼13.5, 3.3 Hz,
1H), 2.69–2.84 (m, 6H), 3.33–3.40 (m, 1H), 3.55 (s, 3H),
4.63 (m, 1H), 5.51 (m, 1H); 13C NMR (75 MHz, CDCl3)
20.2 (CH3), 29.1 (CH2), 29.4 (CH2), 41.6 (CH2), 50.8
(CH), 53.7 (CH3), 73.1 (CH), 90.2 (CH), 120.2 (CH),
132.4 (C), 152.6 (C).

M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
9171
3.1.8. (2S,3S)-3-Methoxy-4-(4-methoxy-2,5-dihydro-
phenyl)-2-butanamine (6b). Operating as above, starting
from 5b (611 mg, 2.92 mmol), 6b was obtained (620 mg)
as an oil, which was used directly in the next step.
1H NMR (200 MHz, CDCl3) 1.09 (d, J¼6.6 Hz, 3H),
2.14–2.29 (m, 2H), 2.74–2.84 (m, 3H), 2.87–2.96 (m, 1H),
3.02–3.07 (m, 1H), 3.40 (s, 3H), 3.55 (s, 3H), 4.62 (m,
1H), 5.49 (m, 1H); 13C NMR (50 MHz, CDCl3) 20.1
(CH3), 29.2 (CH2), 30.0 (CH2), 37.9 (CH2), 49.3 (CH),
53.9 (CH3), 58.4 (CH3), 84.7 (CH), 90.4 (CH), 120.1
(CH), 132.6 (C), 152.9 (C).
6 Hz, H-6ax), 2.26 (dm, J¼14.8 Hz, H-8), 2.32 (dddd,
J¼14, 4.8, 2.4, 2.4 Hz, H-6eq), 2.61 (dd, J¼14.8, 5.6 Hz,
H-8), 2.63 (qd, J¼14, 4.2 Hz, H-5ax), 2.78 (qd, J¼6.5,
2.4 Hz, H-2ax), 3.05 (q, J¼2.7 Hz, H-3eq), 3.30 (masked,
H-8a), 3.31 (s, 3H, OMe); 13C NMR (100 MHz, CDCl3,
gHSQC) 18.1 (Me), 26.9 (C-5), 30.9 (C-4), 33.4 (C-4a),
41.4 (C-6), 47.6 (C-8), 56.3 (C-2), 56.9 (OMe), 58.7 (C-
8a), 76.9 (C-3), 210.6 (C-7). HRMS (ESI-TOF) calcd for
C11H20NO2 (M++1) 198.1489, found 198.1487.
3.1.10.2. (2S,3S,4aS,8aS)-3-Methoxy-2-methyldecahy-
droquinolin-7-one (8b). Colourless oil; Rf ¼0.19 (Al2O3,
99:1 CH2Cl2 saturated with NH3/MeOH); 1H NMR
(400 MHz, CDCl3, gCOSY) 1.11 (d, J¼6.8 Hz, 3H, Me),
1.75–2.00 (m, 4H, H-4, H-5), 2.20–2.30 (m, 3H, H-4a, H-
6), 2.39 (ddd, J¼14.4, 4.4, 1.5 Hz, H-8eq), 2.62 (dd,
J¼14.4, 10 Hz, H-8ax), 3.13 (qd, J¼6.5, 3.2 Hz, H-2ax),
3.34 (masked, H-3eq), 3.36 (s, 3H, OMe), 3.43 (ddd,
J¼10, 4.8, 4.8 Hz, H-8a); 13C NMR (100 MHz, CDCl3,
gHSQC) 16.0 (Me), 27.6 (C-5), 27.8 (C-4), 29.6 (C-4a),
37.7 (C-6), 43.7 (C-8), 48.1 (C-2), 53.3 (C-8a), 56.7
(OMe), 76.4 (C-3), 210.9 (C-7). HRMS (ESI-TOF) calcd
for C11H20NO2 (M++1) 198.1489, found 198.1487.
3.1.9. Aminocyclization of 6a. A solution of 6a (95 mg,
0.48 mmol) in 2 N HCl (1.6 mL) was stirred for 3.5 h at
70 ꢀC. The mixture was basified with NaOH (1 N, 10 mL)
and the solution was extracted with CH2Cl2 (4ꢂ10 mL)
and CHCl3/MeOH (4ꢂ10 mL), dried and concentrated to
give a brown oil. Purification by chromatography (Al2O3,
CH2Cl2 saturated with NH3) gave a partially separated
2.5:1 mixture of 7a (37 mg, 43%) and 8a (15 mg, 17%).
3.1.9.1.
(2S,3S,4aR,8aR)-3-Hydroxy-2-methylocta-
hydroquinolin-7-one (7a). White solid; mp 112–114 ꢀC;
Rf ¼0.17 (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH);
1H NMR (400 MHz, CDCl3, gCOSY) 1.11 (d, J¼6.8 Hz,
3H, Me), 1.81 (ddd, J¼14.8, 5.6, 3.6 Hz, H-4eq), 1.87 (dm,
J¼14 Hz, H-5eq), 1.95 (dt, J¼14.4, 2 Hz, H-4ax), 2.05 (m,
H-4a), 2.24 (dt, J¼14.4, 2 Hz, H-6eq), 2.29 (dd, J¼14.4,
5.6 Hz, H-8ax), 2.32 (m, H-6ax), 2.50 (qd, J¼13.6, 4.8 Hz,
H-5ax), 2.65 (ddd, J¼14.8, 4.8, 0.8 Hz, H-8eq), 2.80 (qd,
J¼6.6, 2 Hz, H-2ax), 3.35 (br s, H-8a), 3.58 (q, J¼2.4 Hz,
H-3eq); 13C NMR (100 MHz, CDCl3, gHSQC) 18.1 (Me),
28.8 (C-5), 33.5 (C-4a), 36.4 (C-4), 41.6 (C-6), 47.5 (C-8),
56.8 (C-8a), 59.3 (C-2), 68.2 (C-3), 210.8 (C-7). HRMS
(ESI-TOF) calcd for C10H18NO2 (M++1) 184.1332, found
184.1337.
3.1.11. (2S,3S,4aR,8aR)-1-Benzoyl-3-hydroxy-2-methyl-
octahydroquinolin-7-one (9a). A solution of 7a (12 mg,
0.07 mmol) was dissolved in THF (0.2 mL) and H2O
(0.2 mL) was added. Then, K2CO3 (39 mg, 0.28 mmol)
and BzCl (8.4 mL, 0.074 mmol) were added. The reaction
mixture was stirred for 2 h at rt, extracted with CH2Cl2
(4ꢂ15 mL), dried and concentrated to give a brown oil. Pu-
rification by column chromatography (Al2O3, from CH2Cl2
saturated with NH3 to 98:2 CH2Cl2 saturated with NH3/
MeOH) gave 9a (19 mg, 99%). Rf ¼0.44 (Al2O3, 98:2
1
CH2Cl2 saturated with NH3); H NMR (300 MHz, CDCl3,
mixture of rotamers) 1.20 and 1.30 (2br d, CH3), 1.70–
2.20 (m, 6H), 2.34 (br, 1H), 2.75 (m, 1H), 3.85–4.15 (br,
2H), 5.07 (br, 1H), 7.25–7.45 (m, 5H, ArH); 13C NMR
(75 MHz, CDCl3) 14.1 and 15.7 (CH3), 27.5 and 28.6 (C-
4), 29.7 (C-5), 31.9 (C-4a), 36.2 (C-6), 49.1 (C-8), 53.4
(C-2), 55.3 (C-8a), 74.6 (C-3), 125.9, 128.8, 129.5, 136.5
(Ar), 171.6 and 172.2 (NCO), 208.0 (C-7). HRMS (ESI-
TOF) calcd for C17H22NO3 (M++1) 288.1594, found
288.1585.
3.1.9.2.
(2S,3S,4aS,8aS)-3-Hydroxy-2-methylocta-
hydroquinolin-7-one (8a). Colourless oil; Rf ¼0.14
(Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH); 1H NMR
(300 MHz, CDCl3) 1.10 (d, J¼6.6 Hz, 3H, Me), 1.72–1.98
(m, 4H), 2.15–2.44 (m, 4H), 2.93 (t, J¼12.6 Hz, H-8ax),
3.06 (qd, J¼6.5, 1.8 Hz, H-2ax), 3.39 (dt, J¼11.7, 4.8 Hz,
H-8a), 3.76 (br s, H-3eq); 13C NMR (75 MHz, CDCl3,
DEPT) 17.7 (Me), 28.0 (C-5), 28.1 (C-4a), 31.9 (C-4), 36.6
(C-6), 42.6 (C-8), 47.5 (C-2), 55.9 (C-8a), 68.2 (C-3),
210.9 (C-7). HRMS (ESI-TOF) calcd for C10H18NO2
(M++1) 184.1332, found 184.1331.
3.1.12. (2S,3S,4aR,8aR)-1-Benzoyl-3-methoxy-2-methyl-
octahydroquinolin-7-one (9b). Operating as above, starting
from 7b (16 mg, 0.08 mmol) and after purification by chro-
matography (Al2O3, CH2Cl2 saturated with NH3), amide 9b
(24 mg, 99%) was obtained as a white solid. Mp 100–
3.1.10. Aminocyclization of 6b. Following the above proce-
dure for the aminocyclization of 6a using methoxy deriva-
tive 6b (225 mg, 1.07 mmol), heating at 70 ꢀC for 3 h and
purifying by chromatography (Al2O3, 99:1 CH2Cl2 saturated
with NH3/MeOH), a partially separated mixture of 7b
(36 mg, 17%) and 8b (50 mg, 22%) was obtained.
1
102 ꢀC; Rf ¼0.52 (Al2O3, CH2Cl2 saturated with NH3); H
NMR (300 MHz, CDCl3, mixture of rotamers) 1.05 and
1.25 (2br d, CH3), 1.70–2.20 (m, 6H), 2.35 (br, 1H), 2.75
(m, 1H), 3.20 and 3.40 (2s, 3H, OCH3), 3.25–3.45 (masked,
2H), 3.95 (br, 0.5H), 4.15 (br, 0.5H), 5.0 (br, 0.5H), 5.20 (br,
0.5H), 7.20–7.65 (m, 4H, ArH), 8.20 (d, J¼7.5 Hz, 1H,
ArH); 13C NMR (75 MHz, CDCl3) 15.0 and 16.0 (CH3),
25.3 and 25.7 (C-4), 27.6 (C-5), 32.6 and 33.5 (C-4a), 36.0
and 36.4 (C-6), 43.6 and 45.2 (C-8), 45.4, 49.4, 51.2 and
56.2 (C-2 and C-8a), 55.6 and 56.6 (OCH3), 77.9 and 78.4
(C-3), 125.7, 128.7, 129.4, 136.6 (Ar), 171.6 (NCO), 207.4
and 207.9 (C-7). HRMS (ESI-TOF) calcd for C18H24NO3
(M++1) 302.1751, found 302.1752.
3.1.10.1. (2S,3S,4aR,8aR)-3-Methoxy-2-methyldeca-
hydroquinolin-7-one (7b). White solid; mp 45–47 ꢀC;
Rf ¼0.25 (Al2O3, 99:1 CH2Cl2 saturated with NH3/MeOH);
1
[a]2D5 +14.6 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3,
gCOSY) 1.12 (d, J¼6.8 Hz, 3H, Me), 1.62 (ddd, J¼14.8,
5.6, 3.2 Hz, H-4eq), 1.74 (m, H-5eq), 2.00 (dm, J¼12 Hz,
H-4a), 2.13 (dt, J¼14.8, 2.2 Hz, H-4ax), 2.23 (td, J¼14,

9172
M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
7. For studies of decahydroquinol-7-ones by this strategy in the
racemic series, see Ref. 6. For other synthesis of decahydro-
quinoline derivatives by intramolecular aza-Michael ring
closure upon cyclohexenones, see: Taber, D. F.; Joshi, P. V.;
Kanai, K. J. Org. Chem. 2004, 69, 2268–2271.
8. (a) For Lepadin A, see: Steffan, B. Tetrahedron 1991, 47, 8729–
8732; (b) For Lepadins B and C, see: Kubanek, J.; Williams,
D. E.; de Silva, E. D.; Allen, T.; Anderson, R. J. Tetrahedron
Lett. 1995, 36, 6189–6192; (c) For Lepadins D–F, see:
3.1.13. (2S,3S,4aR,8aR)- and (2S,3S,4aS,8aS)-1-Benzoyl-
3-methoxy-2-methyloctahydroquinolin-7-one (9b and
10b). A solution of 6b (90 mg, 0.42 mmol) in 2 N HCl
(2 mL) was stirred for 3 h at 75 ꢀC. The mixture was basified
with K2CO3 (464 mg, 3.36 mmol) and BzCl (0.06 mL,
0.5 mmol) in THF (2 mL) was added. The reaction mixture
was stirred for 2 h at rt, concentrated and extracted with
CH2Cl2 (4ꢂ20 mL). The dried organic layers were concen-
trated to give a brown oil, which was purified by chromato-
graphy (SiO2, from hexane/EtOAc 7:3 to EtOAc) to give
a 1:2.3 mixture of 9b (22 mg, 17% from 4b) and 10b
(50 mg, 39% from 4b). For data of 9b, see above.
€
Wright, A. D.; Goclik, E.; Konig, G. M.; Kaminsky, R.
J. Med. Chem. 2002, 45, 3067–3072; (d) For Lepadins F–H,
see: Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod.
2002, 65, 454–457.
9. (a) Toyooka, N.; Okumura, M.; Takahatam, H. J. Org. Chem.
1999, 64, 2182–2183; (b) Toyooka, N.; Okumura, M.; Takaha-
tam, H.; Nemoto, H. Tetrahedron 1999, 55, 10673–10684.
10. (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.
11. Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222–4225.
12. Kalai, C.; Tate, E.; Zard, S. Z. Chem. Commun. 2002, 1430–
1431.
Compound 10b: colourless oil; Rf ¼0.14 (SiO2, 1:1 hexane/
1
EtOAc); [a]2D5 +16 (c 1.2, CHCl3); H NMR (400 MHz,
CDCl3, gCOSY) 1.25 (d, J¼6.8 Hz, 3H, Me), 1.80 (m, H-
5), 1.87 (m, H-4), 1.99 (dt, J¼14, 5.2 Hz, H-4eq), 2.11
(dddd, J¼12, 11, 9.4, 4.4 Hz, H-5ax), 2.25 (ddd, J¼15.4,
10, 5.4 Hz, H-6ax), 2.36 (m, H-4a), 2.64 (masked, 1H, H-
6), 2.59 and 2.67 (2dd, J¼16.8, 5.6 Hz, 1H each, H-8),
3.20 (s, 3H, OMe), 3.51 (ddd, J¼10.8, 5.4, 5.4 Hz, H-3ax),
4.12 (ddd, J¼5.6, 5.6, 2.8 Hz, H-8a), 4.24 (quint,
J¼6.4 Hz, H-2eq), 7.40 (s, 5H, ArH); 13C NMR
(100 MHz, CDCl3, gHSQC) 12.5 (Me), 26.5 (C-5), 28.5
(C-4), 33.3 (C-4a), 38.5 (C-6), 43.0 (C-8), 51.9 (C-8a),
52.8 (C-2), 56.2 (OMe), 75.0 (C-3), 126.8, 128.6, 130.0,
136.6 (Ar), 173.2 (NCO), 205.4 (C-7). HRMS (ESI-TOF)
calcd for C18H24NO3 (M++1) 302.1751, found 302.1750.
13. For a previous work in this field, see: Mena, M.; Bonjoch, J.
Tetrahedron 2005, 61, 8264–8270.
14. (a) Sato, S.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2003, 5, 3839–
3842; (b) Cassidy, M. P.; Padwa, A. Org. Lett. 2004, 6, 4029–
4031; (c) Tsai, M.-R.; Chen, B.-F.; Cheng, C.-C.; Chang, N.-C.
J. Org. Chem. 2005, 70, 1780–1785; (d) Lemire, A.; Charette,
A. B. Org. Lett. 2005, 7, 4029–4031.
15. For a review in the chemistry of N,N-dibenzylamino aldehydes,
see: Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162.
16. For the formation of syn-amino alcohols in the reduction of
N,N-dibenzyl a-alkyl-a-amino ketones, see: Hart, S. A.;
Sabat, M.; Etzkorn, F. A. J. Org. Chem. 1998, 63, 7580–7581.
17. For a review in the chemistry of N-protected-a-amino alde-
hydes, see: Gryko, D.; Chalko, J.; Jurczak, J. Chirality 2003,
15, 514–541.
Acknowledgements
This research was supported by the MEC (Spain)-FEDER
through project CTQ2004-04701/BQU. Thanks are also
due to the DURSI (Catalonia) for Grant 2005SGR-00442
and the Ministry of Education and Science (Spain) for fel-
lowships to M.M. and M.B.
18. (a) Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1991, 56, 4370–
4382; (b) Angle, S. R.; Breitenbucher, J. G.; Arnaiz, D. O.
J. Org. Chem. 1992, 57, 5947–5955; (c) Kumar, K. K.; Datta,
A. Tetrahedron 1999, 55, 13899–13906; (d) Randl, S.;
Blechert, S. Tetrahedron Lett. 2004, 45, 1167–1169.
19. Weinreb amide 1, although previously reported,20 was here
reported by reaction of tribenzyl alanine with N,O-dimethyl-
hydroxylamine using isopropylmagnesium chloride according
to a protocol introduced by Williams, J. M.; Jobson, R. B.;
Yasuda, N.; Marchesini, G.; Dolling, U.-H.; Grabowski, E. J. J.
Tetrahedron Lett. 1995, 36, 5461–5464.
20. Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635–3645.
ꢀ
21. Barluenga, J.; Baragan˜a, B.; Concellon, J.-M. J. Org. Chem.
1995, 60, 6696–6699.
22. Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984,
106, 3693–3694.
References and notes
1. (a) Ueda, N.; Tokuyama, T.; Sakan, T. Bull. Chem. Soc. Jpn.
1966, 39, 2012–2014; (b) Bonjoch, J.; Catena, J.; Valls, N.
J. Org. Chem. 1996, 61, 7106–7115.
ꢀ
2. (a) Bonjoch, J.; Catena, J.; Isabal, E.; Lopez-Canet, M.; Valls,
N. Tetrahedron: Asymmetry 1996, 7, 1899–1902; (b) Bonjoch,
ꢀ
ꢀ
ꢀ
J.; Catena, J.; Terricabras, D.; Fernandez, J.-C.; Lopez-Canet,
M.; Valls, N. Tetrahedron: Asymmetry 1997, 8, 3143–3151;
ꢀ
(c) Valls, N.; Lopez-Canet, M.; Vallribera, M.; Bonjoch, J.
Chem.—Eur. J. 2001, 7, 3446–3460.
3. Venit, J. J.; DiPierro, M.; Magnus, P. J. Org. Chem. 1989, 54,
4298–4301.
4. (a) Gensler, W. J.; Gatsonis, C. D.; Ahmed, Q. A. J. Org. Chem.
1968, 33, 2968–2971; (b) Furstoss, R.; Esposito, G.; Teissier,
P.; Waegell, B. Bull. Soc. Chim. Fr. 1974, 2485–2494.
5. Adachi, J.; Nomura, K.; Mitsuhashi, K. Chem. Pharm. Bull.
1976, 24, 85–91.
23. For a precedent, in the ring-opening of epoxide 3 by an organo-
lithium reagent in the presence of BF3$Et2O, see Ref. 13. For
the reductive alkylation of epoxide 3 with organolithium
ꢀ
ꢀ
reagents, see: Concellon, J. M.; Suarez, J. R.; Del Solar, V.
6. (a) Momose, T.; Uchida, S.; Kinoshita, M.; Imanishi, T.
Chem. Pharm. Bull. 1977, 25, 1797–1802; (b) Momose, T.;
Uchida, S.; Kinoshita, M.; Imanishi, T. Chem. Pharm. Bull.
Org. Lett. 2006, 8, 349–351.
OH
€
1978, 26, 620–626; (c) Liu, D.; Wikstrom, H. V.; Dijkstra,
D.; deVries, J. B.; Venhuis, B. J. J. Med. Chem. 2006, 49,
1494–1498.
epi-4a
24.
MeO
Me
NBn2

M. Mena et al. / Tetrahedron 62 (2006) 9166–9173
9173
25. Reetz, M. T.; Drewes, M. W.; Lennick, K.; Schmitz, A.;
€
Torres, J. A.; Snelling, R. R.; Jones, T. H. J. Nat. Prod. 1999,
62, 5–21; (d) Phuan, P.-W.; Kozlowski, M. C. J. Org. Chem.
2002, 67, 6339–6346.
Holdgrun, X. Tetrahedron: Asymmetry 1990, 1, 375–378.
26. 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.;
27. (a) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1141–1143; (b) Reetz, M. T.;
Drewes, M. W.; Schwickardi, R. Org. Synth. 1999, 76,
110–122.