Synthesis of 2,5-disubstituted octahydroquinolin-4-ones via an intramolecular hetero Diels-Alder reaction

Article abstract of DOI:10.3390/12020194

A route for the preparation of 2,5-disubstituted octahydroquinolin-4-ones, synthetic precursors of the decahydroquinoline-type toxins, is presented. The key steps are an asymmetric epoxidation and an intramolecular hetero Diels-Alder reaction between an a

Full text of DOI:10.3390/12020194

Molecules 2007, 12, 194-204
molecules
ISSN 1420-3049
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Full Paper
Synthesis of 2,5-Disubstituted Octahydroquinolin-4-ones via an
Intramolecular Hetero Diels-Alder Reaction
Juan M. Ruiz, María M. Afonso and J. Antonio Palenzuela*
Instituto Universitario de Bio-Orgánica “Antonio González”, Departamento de Química Orgánica,
Universidad de La Laguna, 38206 La Laguna, Tenerife, Spain
* Author to whom correspondence should be addressed. E-mail: jpalenz@ull.es
Received: 25 January 2007; in revised form: 13 February 2007 / Accepted: 13 February 2007 /
Published: 19 February 2007
Abstract: A route for the preparation of 2,5-disubstituted octahydroquinolin-4-ones,
synthetic precursors of the decahydroquinoline-type toxins, is presented. The key steps
are an asymmetric epoxidation and an intramolecular hetero Diels-Alder reaction
between an activated diene and an imine. The presence of an allylic stereogenic center
induces some selectivity and thus only two cycloadducts are obtained in 70:30 ratio and
good yield.
Keywords: Hetero Diels-Alder, alkaloids, octahydroquinolone
Introduction
Interest in the biological activity of the analogs of naturally occurring toxins, such as those isolated
from skin extracts of dendrobatid frogs [1], has prompted the development of new synthetic strategies
or has led to the improvement of older ones for these targets [2]. One of the most powerful strategies is
based on intramolecular Diels-Alder reactions, which have been used in different approaches, usually
with high selectivity [3]. Grieco and Parker [4] have presented a synthesis of (-)-8a-epi-pumiliotoxin
based on an hetero Diels-Alder reaction between a diene and an imine carried out under Mannich
conditions and they found that the selectivity of the process can be influenced by an allylic substituent.
Within a project aimed at the synthesis of bicyclic alkaloids, we were interested in the
development of a synthetic strategy for the preparation of 2,5-disubstituted decahydroquinolines [1],
which could allow us to prepare different analogs of the natural toxins. We envisioned that the basic

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skeleton could be constructed by the intramolecular hetero Diels-Alder reaction of a suitable precursor
containing a diene and an imine, in an approach similar to the one used by Grieco and Parker [4].
For our synthesis, and in order to increase the reactivity, we decided to place an activating group
such as a tert-butyldimethylsilyloxy moiety on the diene, in such a position as to favor the desired
regiochemistry of the process. To achieve the required substitution pattern, a substituent is needed at
the allylic position and, in order to have a more flexible synthesis, it must be possible to transform said
substituent into the different functional groups present in the natural toxins. Thus, it was decided to
place a protected hydroxy group at the allylic position. It was also expected that the 1,3-non-bonded
interaction between that substituent and the silyloxy group would increase the selectivity of the
process by favoring one of the possible reacting conformations [5]. Therefore, the goal of this work
was to establish a synthetic route to an activated diene-imine system, such as the one shown in Scheme
1, and to test its reactivity under hetero Diels-Alder reaction conditions.
Scheme 1
R2
OP' OTBDMS
NP R1
N
R1
H
Results and Discussion
In order to achieve this goal, and to do so in an enantioselective way, we decided to use the
Katsuki-Sharpless asymmetric epoxidation reaction [6] as the source of the allylic stereogenic center,
and thus the allylic alcohol 1, which can be prepared easily from 1,5-pentanediol [7] was selected as
our starting compound. The asymmetric epoxidation gave the expected epoxide 2 in good yield and
high enantioselectivity, and in the subsequent steps it was regioselectively opened to give a diol. The
secondary hydroxy group was then protected as the corresponding methoxymethyl ether by first
masking the primary one as the bulky pivaloyl ester. Finally, the pivaloyl group was removed, yielding
6 (Scheme 2).
Scheme 2
OR2
O
a
b
OH
OH
OR1
OTBDPS
OTBDPS
OTBDPS
3 R1 = R2 = H
1
2
c
d
e
4 R1 = Piv; R2 = H
5 R1 = Piv; R2 = MOM
6 R1 = H; R2 = MOM
Reagents: (a) (+)-diethyl tartrate, Ti(OiPr)4, t-BuOOH, CH2Cl2, MS 4Å (90%); (b) Red-Al, THF,
0ºC to r.t. (95%); (c) PivCl, Py, 0ºC to r.t. (88%); (d) MOMCl, i-Pr2NEt, 0ºC to r.t. (82%); (e)
DIBAL, Et2O, -60ºC (100%)

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196
Oxidation of 6 and treatment with the anion of benzyl protected homopropargyl alcohol allowed
the construction of 7, which has the carbon skeleton of the target compound. In order to transform 7
into the desired compound, and after several attempts, the following sequence was found to be the
most efficient: partial reduction of the triple bond, removal of the silicon protecting group and
selective oxidation of the allylic alcohol formed to give the α, β-unsaturated ketone 9, precursor of the
activated diene system (Scheme 3).
Scheme 3
MOMO
OH
MOMO
OH
c
a, b
OBn
6
OBn
OTBDPS
OTBDPS
7
8
d, e
MOMO
O
OBn
OH
9
Reagents: (a) Oxalyl chloride, DMSO, -78ºC, Et3N; (b) n-BuLi, HC≡CCH2CH2OBn, THF, -78ºC
to r.t. (88% from 6); (c) LiAlH4 (80%) THF, reflux; (d) TBAF, THF, 0ºC to r.t. (87%); (e) MnO2,
CH2Cl2, r.t. (81%)
After acetylation of the primary hydroxy group the compound 10 containing the activated diene
system was prepared by LDA enolization of the α,β-unsaturated ketone 9, in a process hindered by
side reactions such as elimination of the -OMOM group or the abstraction of the γ proton instead of the
α one. The last step on the synthesis was the transformation of the acetylated primary hydroxy group
into the imine, and this was achieved by reductive deprotection of the acetate and SO3·Py oxidation of
the free hydroxy group to give the aldehyde 11, which was pure enough to be used without
purification. When 11 was subjected to column chromatography, it was obtained pure, but in only a
40% yield (Scheme 4).
Scheme 4
MOMO
OTBDMS
O
MOMO
OTBDMS
c, d
OBn
a, b
OBn
9
OAc
11
10
Reagents: (a) Ac2O, Py, 0ºC to r.t. (99%); (b) LDA, TBDMSOTf, THF, -78ºC (62%); (c) DIBAL,
Et2O, -70ºC (76%); (d) SO3·Py, DMSO, Et3N, 0ºC to r.t. (40%)

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The cycloaddition reaction was carried out by first converting 11 into an imine by treatment with
benzylamine in the presence of anhydrous magnesium sulfate and, without purification, the crude
reaction mixture was dissolved in CH3CN and indium triflate was added as the Lewis acid. This way,
two compounds were isolated in a 70:30 ratio and 79% yield and their structures were established
spectroscopically. Both compounds presented the structure expected for the cycloadducts, differing
only in the relative stereochemistry at the newly formed stereogenic centers. The major compound 12,
results from the exo approach of the imine to the diene portion of the molecule in the most favorable
conformation, whereas the minor one 13 arises from the endo approach. The relative stereochemistry
was deduced from goesy experiments on 12 and 13 [8] and was confirmed, using also goesy
experiments, on the more stable decahydroquinolone 14, prepared from 12 by treatment with tetrabutyl
ammonium fluoride (Scheme 5).
Scheme 5
MOMO
OTBDMS
MOMO
OTBDMS
H
H
H
H
a, b
+
11
N
OBn
N
OBn
H
H
Bn
Bn
70:30
12
13
c
MOMO
O
H
N
OBn
H
H
Bn
14
Reagents: (a) BnNH2, MgSO4, Et2O, 0ºC; (b) In(OTf)3, CH3CN, 0ºC to r.t. (79%); (c) TBAF,
THF, 0ºC to r.t. (90%)
The isolated yield in our case (79%) was higher than that reported by Grieco and Parker [4] (55%),
which may be due to the activation provided by the silyloxy group, but the selectivity of the process is
similar to that previously described, affording the two cycloadducts in a 70:30 ratio and with the same
relative stereochemistry in both of them.
Conclusions
In summary, an enantioselective route to the octahydroquinolinone skeleton with substitution on the
2 and 5 positions has been described. The key steps are a Katsuki-Sharpless asymmetric epoxidation,
used for the introduction of the controlling stereogenic center, and an intramolecular hetero Diels-
Alder reaction of a molecule containing an activated diene and an imine. The resulting cycloadducts
can be used for the synthesis of analogs of naturally occurring toxins of the 2,5-decahydroquinoline
family.

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Experimental
General
13
1H-NMR and C-NMR spectra were recorded in CDCl3 or C6D6 at 400 MHz (1H) and 100 MHz
(13C) on a Bruker AVANCE 400 instrument. The chemical shifts are quoted in ppm using the residual
solvent signal as reference. Multiplicities were determined by DEPT experiments. IR spectra were
recorded using a Shimadzu 408 spectrophotometer. Optical rotations were determined using a Perkin-
Elmer 241 polarimeter. Mass spectra were run on a VG (Fisons) spectrometer. Flash chromatography
was performed on columns packed with Merck silica gel 60 (260-400 mesh). Solvents and reagents
were generally distilled prior to use, and purified when necessary according to standard procedures.
Preparation of ((2S, 3S)-3-(4-(tert-butyldiphenylsilyloxy)butyl)oxiran-2-yl)methanol (2)
To a mixture of crushed molecular sieves (MS 4Å) and (+)-DET (3.06 mL, 17.8 mmol) in dry
CH2Cl2 under argon at -20 ºC was added Ti(OPr-i)4 (4.52 mL, 15.32 mmol). After 15 min, compound 1
was added (4.7 g, 12.77 mmol), and 30 min later, a 5.3 M solution of TBHP in benzene (4.3 mL, 23
mmol) was added. The reaction was stirred at -20ºC overnight. The reaction was quenched by the
addition of tartaric acid solution (15% in water), and further extraction was done with CH2Cl2 (3 × 50
mL). The combined organic extracts were dried (MgSO4), concentrated, and chromatographed on
silica gel (70:30 Hex-EtOAc) yielding 4.4 g (90%) of 2 as a colorless oil; [α] 2D5 = -14.23 (c 2.08,
1
CHCl3); H- NMR (CDCl3) δ 7.70-7.68 (m, 4H), 7.43-7.38 (m, 6H), 3.90 (dd, J = 1.7 Hz, 12.5 Hz,
1H), 3.69 (m, 2H), 3.60 (dd, J = 4.4 Hz, 12.5 Hz, 1H), 3.50 (bs, 1H), 2.95-2.91 (m, 2H), 1.64-1.57 (m,
6H), 1.08 (s, 9H); 13C-NMR (CDCl3) δ 135.6 (d), 134.0 (s), 129.6 (d), 127.6 (d), 63.6 (t), 61.8 (t), 58.6
(d), 56.0 (d), 32.2 (t), 31.3 (t), 26.9 (q), 22.3 (t), 19.2 (s).
Preparation of (S)-7-(tert-butyldiphenylsilyloxy)heptane-1,3-diol (3)
To a solution of 2 (4.2 g, 10.9 mmol) in THF (110 mL) at 0 ºC under argon was added Red-Al
(9.19 mL, 32.9 mmol, 70%). The reaction was allowed to reach room temperature and stirred for 5 h.
The reaction mixture was quenched at 0 ºC by slowly addition of MeOH (1.5 mL). The solution was
poured into an aqueous saturated solution of potassium sodium tartrate and it was vigorously stirred
until the phases became clear. After phase separation, the combined organic extracts were dried
(MgSO4), concentrated, and chromatographed on silica gel (60:40 Hex-EtOAc) yielding 4.0 g (95%)
1
of 3 as a colorless oil; H-NMR (CDCl3) δ 7.69-7.68 (m, 4H), 7.43-7.37 (m, 6H), 3.68-3.67 (m, 3H),
3.71-3.67 (m, 2H), 3.25 (m, 2H), 1.67-1.58 (m, 2H), 1.51-1.41 (m, 4H), 1.07 (s, 9H); 13C-NMR
(CDCl3) δ 135.6 (d), 134.0 (s), 129.6 (d), 127.6 (d), 72.0 (d), 63.8 (t), 61.6 (t), 38.0 (t), 37.4 (t), 32.4
(t), 26.9 (q), 21.8 (t), 19.2 (s); EIMS m/z (%): 329 (M+-tBu, 0.1), 311 (M+-tBu-H2O, 0.57); HRMS
(EI): C19H25O3Si (M+-tBu): 329.1573, found 329.1577.

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Preparation of (S)-7-(tert-butyldiphenylsilyloxy)-3-hydroxyheptyl pivalate (4)
To a solution of 3 (1.95 g, 5.05 mmol) in pyridine (2.0 mL) at 0ºC under argon, was added pivaloyl
chloride (0.68 mL, 5.55 mmol). The reaction mixture was stirred at room temperature until TLC
showed disappearance of the starting material. The reaction was diluted with Et2O and then ice and
finally a saturated aqueous solution of NaCl was added. The mixture was extracted with Et2O (3 × 20
mL). The combined organic layers were dried (MgSO4), concentrated, and chromatographed on silica
gel (85:15 Hex-EtOAc) yielding 2.1 g (88%) of 4 as a colorless oil; [α] 2D5 = +1.08 (c 3.5, CHCl3); 1H-
NMR (CDCl3) δ 7.71-7.76 (m, 4H), 7.45-7.38 (m, 6H), 4.35 (m, 1H), 4.16 (m, 1H), 3.71 (t, J = 6.0
Hz, 2H), 3.66 (m, 1H), 2.45 (s, 1H), 1.84-1.80 (m, 1H), 1.70-1.52 (m, 7H), 1.20 (s, 9H), 1.04 (s, 9H);
13C-NMR (CDCl3) δ 179.0 (s), 135.6 (d), 134.0 (s), 129.6 (d), 127.6 (d), 68.6 (d), 63.8 (t), 61.7 (t),
38.8 (s), 37.1 (t), 36.4 (t), 32.0 (t), 27.2 (q), 26.9 (q), 21.9 (t), 19.2 (s); EIMS m/z (%): 413 (M+-tBu,
5.0), 395 (M+-tBu-H2O, 2.0); HRMS (EI): C24H33O4Si (M+-tBu): 413.2148, found 413.2174.
Preparation of (S)-7-(tert-butyldiphenylsilyloxy)-3-(methoxymethoxy)heptyl pivalate (5)
To a solution of 4 (2.1 g, 4.46 mmol) in i-Pr2NEt (1.16 mL) at 0ºC under argon, was added
MOMCl (0.37 mL, 4.91 mmol). The reaction mixture was stirred at room temperature until TLC
showed disappearance of the starting material (2 h). The reaction was diluted with Et2O and then ice
and a saturated aqueous solution of NaCl were added. The mixture was extracted with Et2O (3 × 50
mL). The combined organic layers were dried (MgSO4), concentrated, and chromatographed on silica
gel (95:5 Hex-EtOAc) yielding 1.89 g (82%) of 5 as a colorless oil; [α] 2D5 = +12.13 (c 2.06, CHCl3);
1H-NMR (CDCl3) δ 7.69-7.67 (m, 4H), 7.43-7.37 (m, 6H), 4.64 (d, J = 6.9 Hz, 1H), 4.62 (d, J = 6.9
13
Hz, 1H), 4.18 (m, 2H), 3.66 (m, 3H), 3.36 (s, 3H), 1.85-1.40 (m, 8H), 1.21 (s, 9H), 1.06 (s, 9H); C-
NMR (CDCl3) δ 178.5 (s), 135.6 (d), 134.0 (s), 129.5 (d), 127.6 (d), 95.6 (t), 74.4 (d), 63.7 (t), 61.2 (t),
55.6 (q), 38.7 (s), 34.3 (t), 33.4 (t), 32.6 (t), 27.2 (q), 26.9 (q), 21.5 (t), 19.2 (q); EIMS m/z (%): 457
(M+-tBu, 3.1); HRMS (EI): C26H37O5Si (M+-tBu): 457.2410, found 457.2404.
Preparation of (S)-7-(tert-butyldiphenylsilyloxy)-3-(methoxymethoxy)heptan-1-ol (6)
DIBAL (1M in hexanes, 11 mL, 11 mmol) was added to a solution of 5 (1.89 g, 3.67 mmol) in
Et2O (129 mL) under argon at -60ºC. After stirring for 2 h, MeOH (5 mL) was slowly added and the
reaction mixture was allowed to reach room temperature. Then it was poured onto a saturated aqueous
solution of sodium potassium tartrate, stirred until the solution becomes clear and extracted with Et2O.
The combined organic layers were dried (MgSO4) and concentrated, affording after column
chromatography (silica gel, 70:30 Hex-EtOAc), 1.58 g (100%) of alcohol 6, as a colorless oil; [α] 2D5
=
1
+22.67 (c 2.67, CHCl3); H-NMR (CDCl3) δ 7.68-7.61 (m, 4H), 7.43-7.36 (m, 6H), 4.67 (d, J = 6.8
Hz, 1H), 4.65 (d, J = 6.8 Hz, 1H), 3.81-3.65 (m, 4H), 3.39 (s, 3H), 1.67-1.40 (m, 8H), 1.04 (s, 9H);
13C-NMR (CDCl3) δ 135.6 (d), 134.0 (s), 129.6 (d), 127.6 (d), 95.9 (t), 76.4 (d), 63.7 (t), 59.8 (t), 55.7
(q), 35.6 (t), 34.4 (t), 32.6 (t), 26.9 (q), 21.6 (t), 19.2 (s); EIMS m/z (%): 342 (M+-tBu-OCH3, 1.85).

Molecules 2007, 12
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(7S)-1-(benzyloxy)-11-(tert-butyldiphenylsilyloxy)-7-(methoxymethoxy)undec-3-yn-5-ol (7)
To a solution of DMSO (0.63 mL, 8.98 mmol) in CH2Cl2 (30 mL) under argon at -78ºC was slowly
added a solution of oxalyl chloride (2 M in CH2Cl2, 2.24 mL, 4.48 mmol). After 30 min the alcohol 6
(1.61 g, 3.74 mmol) was added in CH2Cl2 (10 mL). After the mixture was stirred for 1 h, TEA (2.6
mL, 18.7 mmol) was added, and the reaction was allowed to reach to room temperature. Water was
added, and the reaction was extracted with CH2Cl2. The combined organic extracts were washed with
10 mL each of 1 % aqueous solution of HCl, 5 % Na2CO3, and a saturated solution of NaCl. The
solution was dried (MgSO4) and concentrated. The expected aldehyde was obtained and used without
further purification. To a solution of ((but-3-ynyloxy)methyl)benzene (658 mg, 4.11 mmol) in THF
(15 mL) under argon at -78ºC was added n-BuLi (2.57 mL, 4.11 mmol, 1.6 M in hexane), and the
mixture was stirred for 30 min. Then, a solution of the previously obtained aldehyde in THF (5 mL)
was added. The reaction mixture was allowed to warm to room temperature for 2 h and then it was
quenched by the addition of aqueous saturated NH4Cl solution and extracted with Et2O (3 × 25 mL).
The combined organic extracts were washed with brine, dried (MgSO4) concentrated, and
chromatographed on silica gel (75:25 Hex-EtOAc) yielding 1.93 g (88%) of an inseparable mixture of
diastereomers 7.
(7S,E)-1-(benzyloxy)-11-(tert-butyldiphenylsilyloxy)-7-(methoxymethoxy)undec-3-en-5-ol (8)
A suspension of 131 mg (3.46 mmol) of LiAlH4 in 50 ml of THF was cooled to 0 ºC, and a
solution of 7 (1.7 g, 2.89 mmol) in THF (10 mL) was added dropwise. The reaction mixture was
heated at reflux for 2 h, cooled to 0 ºC and quenched by successive addition of H2O (0.13 mL),
aqueous solution of NaOH 10% (0.13 mL) and H2O (0.4 mL). The mixture was filtered through
Celite®, the residue was washed with EtOAc, the combined filtrates were concentrated, and
chromatographed on silica gel (75:25 Hex-EtOAc) yielding 1.36 g (80%) of an inseparable mixture of
diastereomers 8.
(S,E)-1-(benzyloxy)-11-hydroxy-7-(methoxymethoxy)undec-3-en-5-one (9)
To a solution of 8 (1.4 g, 2.37 mmol) in THF (40 mL) at 0 ºC under argon was added TBAF (1.1
equiv). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The
reaction was quenched by the addition of ice and brine. After extraction with EtOAc (3 × 25 mL), the
combined extracts were dried (MgSO4), concentrated, and chromatographed on silica gel (20:80 Hex-
EtOAc) yielding 726 mg (87%) of the corresponding diol as an inseparable mixture of diastereomers.
To a suspension of MnO2 (6.9 g) in CH2Cl2, under an O2 atmosphere, was added the mixture of
alcohols previously obtained (698 mg, 1.98 mmol) in CH2Cl2 (10 mL). After 12 h the reaction mixture
was filtered through celite and the solution was concentrated and chromatographed on silica gel (30:70
1
Hex-EtOAc) yielding 561 mg (81%) of 9 as a colorless oil; [α] 2D5 = +1.44 (c 3.60, CHCl3); H-NMR
(CDCl3) δ 7.37-7.26 (m, 5H), 6.86 (dt, J = 6.9 Hz, 15.9 Hz, 1H), 6.17 (d, J = 15.9 Hz, 1H), 4.61 (d, J
= 6.9 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.52 (s, 2H), 4.09 (m, 1H), 3.61 (m, 4H), 3.32 (s, 3H), 2.90
(dd, J = 6.9 Hz, 10.0 Hz, 1H), 2.62 (dd, J = 5.9, 10.0 Hz, 1H), 2.55-2.50 (m, 2H), 1.68-1.42 (m 6H);

Molecules 2007, 12
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13C-NMR (CDCl3) δ 198.3 (s), 144.2 (d), 137.7 (s), 131.9 (d), 128.2 (d), 127.5 (d), 127.4 (d), 95.8 (t),
74.1 (d), 72.8 (t), 68.3 (t), 62.2 (t), 55.3 (d), 45.0 (t), 34.5 (t), 32.6 (t), 32.3 (t), 21.1 (t).
Preparation of (S,6Z,8E)-11-(benzyloxy)-7-(tert-butyldimethylsilyloxy)-5-(methoxymethoxy)undeca-
6,8-dienyl acetate (10)
To a solution of 9 (560 mg, 1.6 mmol) in pyridine (0.2 mL) at 0 ºC under argon was added Ac2O
(0.15 mL, 1.6 mmol). The reaction mixture was stirred overnight at room temperature and then ice-
water was added. The mixture was extracted with CH2Cl2 (3 × 15 mL), and the combined organic
phases were dried (MgSO4), concentrated and chromatographed on silica gel (60:40 Hex-EtOAc)
yielding 624 mg (99%) of (S,E)-11-(benzyloxy)-5-(methoxymethoxy)-7-oxoundec-8-enyl acetate as a
1
colorless oil; [α] 2D5 = -0.85 (c 2.60, CHCl3); H-NMR (CDCl3) δ 7.36 (m, 5H), 6.85 (dt, J = 6.8 Hz,
15.9 Hz, 1H), 6.17 (d, J = 15.9 Hz, 1H), 4.64 (d, J = 6.8 Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 4.51 (s,
2H), 4.05 (m, 3H), 3.58 (t, J = 6.3 Hz, 2H), 3.31 (s, 3H), 2.88 (dd, J = 6.8 Hz, 15.9 Hz, 1H), 2.61-2.48
(m, 3H), 2.02 (s, 3H), 1.75-1.38 (m, 6H); 13C-NMR (CDCl3) δ 198.3 (s), 171.1 (s), 144.3 (d), 138.0 (s),
132.1 (d), 128.4 (d), 127.7 (d), 96.1 (t), 74.2 (d), 73.0 (t), 68.2 (t), 64.3 (t), 55.5 (q), 45.3 (t), 34.7 (t),
32.9 (t), 28.6 (t), 21.7 (t), 20.9 (q). tert-Butyldimethylsilyl triflate (0.51 mL, 2.23 mmol) was added to
a stirred solution of the previously prepared compound (624 mg, 1.59 mmol) in THF (16 mL) at -78
ºC under argon. After 15 min a solution of LDA (0.24 M in THF, 7.9 mL, 1.9 mmol) was added. The
reaction mixture was stirred at -78 ºC for 30 min, and then a saturated aqueous solution of NH4Cl (15
mL) was added. The reaction was allowed to reach room temperature and extracted with Et2O. The
combined organic phases were dried (MgSO4), concentrated, and chromatographed on silica gel (80:20
Hex-EtOAc) yielding 500 mg (62%) of 10 as a colorless oil; [α] 2D5 = -49.39 (c 4.90, CHCl3); 1H-NMR
(C6D6) δ 7.37-7.10 (m, 5H), 6.02 (dt, J = 6.7 Hz, 15.9 Hz, 1H), 5.88 (d, J = 15.9 Hz, 1H), 4.86 (d, J =
6.6, 1H), 4.75 (m, 2H), 4.46 (d, J = 6.6 Hz, 1H), 4.28 (s, 2H), 4.04-3.96 (m, 2H), 3.30 (t, J = 6.4 Hz,
2H), 3.24 (s, 3H), 2.30-2.26 (m, 2H), 1.67 (s, 3H), 1.66-1.50 (m, 6H), 0.99 (s, 9H), 0.20 (s, 3H), 0.14
13
(s, 3H); C-NMR (CDCl3) δ 169.5 (s), 150.1 (s), 138.5 (s), 129.7 (d), 128.2 (d), 127.9 (d), 127.4 (d),
113.4 (d), 93.2 (t), 72.4 (t), 69.5 (d), 69.2 (t), 63.7 (t), 54.5 (q), 35.3 (t), 32.6 (t), 28.5 (t), 25.6 (q), 21.9
(t), 19.9 (q), 18.0 (s), -4.1 (q).
Preparation of (S,6Z,8E)-11-(benzyloxy)-7-(tert-butyldimethylsilyloxy)-5-(methoxymethoxy)undeca-
6,8-dienal (11)
To a solution of 10 (500 mg, 0.98 mmol) in Et2O (10 mL) at -70ºC under argon was added DIBAL
(1 M in hexanes, 4.94 mL, 4.94 mmol). The reaction was stirred until TLC showed disappearance of
the starting material (15 min). The reaction mixture was quenched by slowly addition of MeOH (1.0
mL) and the solution was allowed to reach room temperature. The solution was poured into an aqueous
saturated solution of potassium sodium tartrate and it was vigorously stirred until the phases became
clear. After phase separation, the combined organic extracts were dried (MgSO4), concentrated, and
chromatographed on silica gel (70:30 Hex-EtOAc) yielding 345 mg (76%) of (S,6Z,8E)-11-
(benzyloxy)-7-(tert-butyldimethylsilyloxy)-5-(methoxymethoxy)undeca-6,8-dien-1-ol as a colorless
1
oil; H-NMR (C6D6) δ 7.33-7.06 (m, 5H), 6.05-5.98 (m, 1H), 5.85 (d, J = 15.6 Hz, 1H), 4.85 (d, AB
system, J = 6.6 Hz, 1H), 4.75 (m, 2H), 4.47 (d, AB system, J = 6.6 Hz, 1H), 4.27 (s, 2H), 3.45 (t, J =

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6.0 Hz, 2H), 3.27 (t, J = 6.5 Hz, 2H), 3.24 (s, 3H), 2.29-2.23 (m, 2H), 1.78-1.30 (m, 7H), 1.05 (s, 9H),
0.19 (s, 3H), 0.14 (s, 3H); 13C-NMR (C6D6) δ 150.6 (s), 139.1 (s), 130.3 (d), 128.5 (d), 127.8 (d), 127.7
(d), 114.2 (d), 93.8 (t), 72.9 (t), 70.4 (t), 69.8 (t), 62.6 (d), 55.1 (q), 36.1 (t), 33.2 (t), 26.2 (q), 22.4 (t),
18.6 (s), -3.4 (q). To a solution of the previously prepared alcohol (340 mg, 0.73 mmol) in CH2Cl2 (7
mL) under argon at 0 ºC was added TEA (0.5 mL, 3.65 mmol) and DMSO (0.77 mL, 11.0 mmol).
After 15 min SO3·Py (348 mg, 3.65 mmol) was added. The reaction mixture was allowed to reach to
room temperature and stirred for 3 h. Water was added, and the reaction was extracted with Et2O (4 ×
15 mL). The combined organic extracts were washed with brine. The solution was dried (MgSO4) and
1
concentrated. The expected aldehyde 11 was obtained pure enough, according to H-NMR, and was
usually used without further purification. This aldehyde could be purified by column chromatography
on silica gel (80:20 Hex:EtOAc), although the yield was very low due to decomposition.
Hetero Diels-Alder Reaction
To a solution of the previously purified aldehyde 11 (135 mg, 0.29 mmol) in Et2O (0.6 mL) under
argon at 0 ºC were added benzylamine (0.03 mL, 0.29 mmol) and a small amount of anhydrous
MgSO4. After stirring for 30 min the reaction was diluted with pentane, filtered and concentrated. The
crude reaction mixture was dissolved in CH3CN (5.0 mL) and cooled to 0 ºC under argon atmosphere.
Then In(OTf)3 (81.5 mg, 0.145 mmol) in CH3CN (6 mL) was added and the reaction was allowed to
warm to room temperature. After stirring for 12 h, a cold aqueous solution of NaHCO3 was added.
After extraction with Et2O, the combined organic layers were dried (MgSO4), concentrated and
chromatographed on silica gel (90:10 Hex-EtOAc) yielding 127 mg (79%) of a 70:30 mixture of 12
and 13 which were separated by HPLC.
(2R,4aS,5S,8aR)-1-benzyl-2-(2-benzyloxy)ethyl)-4-(tert-butyldimethylsilyloxy)-5-(methoxymethoxy)-
25
1,2,4a,5,6,7,8,8a-octahydroquinoline (12) (major isomer); colorless oil; [α] = -23.08 (c 1.30,
D
1
CHCl3); H-NMR (CDCl3) δ 7.32-7.13 (m, 10H), 4.81 (m, 2H), 4.61 (d, J = 6.9 Hz, 1H), 4.13 (AB
system, J = 11.6, 8.8 Hz, 2H), 3.84 (d, J = 13.3 Hz, 1H), 3.43 (m, 1H), 3.38 (s, 3H), 3.26 (d, J = 13.3
Hz, 1H), 3.22 (m, 1H), 3.08 (m, 1H), 2.67 (m, 1H), 2.15 (m, 2H), 1.80 (m, 1H), 1.75-1.69 (m, 3H),
13
1.60-1.55 (m, 2H), 1.44 (m, 2H), 0.98 (s, 9H), 0.22 (s, 3H), 0.20 (s, 3H); C-NMR (CDCl3) δ 151.5
(s), 140.8 (s), 138.6 (s), 129.1 (d), 128.2 (d), 128.0 (d), 127.8 (d), 127.3 (d), 126.7 (d), 108.0 (d), 97.5
(t), 80.5 (d), 72.7 (t), 68.0 (t), 56.2 (d), 55.3 (q), 53.7 (d), 51.1 (t), 44.2 (d), 35.4 (t), 34.4 (t), 30.4 (t),
26.2 (q), 23.0 (t), 18.7 (s), -4.9 (q).
(2S,4aR,5S,8aR)-1-benzyl-2-(2-benzyloxy)ethyl)-4-(tert-butyldimethylsilyloxy)-5-(methoxymethoxy)-
1
1,2,4a,5,6,7,8,8a-octahydroquinoline (13) (minor isomer); colorless oil; H-NMR (CDCl3) δ 7.35-
7.21 (m, 10H), 4.76-4.74 (m, 1H), 4.64-4.60 (m, 2H), 4.35-4.32 (m, 3H), 3.83 (d, J = 14.0 Hz, 1H),
3.68 (d, J = 14.0 Hz, 1H), 3.50-3.43 (m, 2H), 3.31 (s, 3H), 3.29 (m, 1H), 3.07-3.04 (m, 1H), 2.73 (m,
13
1H), 1.88 (m, 1H), 1.74-1.37 (m, 7H), 0.94 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H); C-NMR (CDCl3) δ
147.3 (s), 140.8 (s), 138.6 (s), 128.6 (d), 128.3 (d), 128.1 (d), 127.7 (d), 127.4 (d), 126.6 (d), 105.4 (d),
95.2 (t), 73.7 (d), 72.9 (t), 68.4 (t), 59.8 (t), 55.4 (d), 55.2 (q), 39.3 (d), 37.1 (t), 29.5 (t), 27.8 (t), 25.7
(q), 20.1 (t), 18.1 (s), -4.9 (q).

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Preparation
of
(2R,4aS,5S,8aR)-1-benzyl-2-(2-benzyloxy)ethyl)-5-(methoxymethoxy)octahydro-
quinolin-4(1H)-one (14)
To a solution of 12 (79 mg, 0.14 mmol) in THF (5 mL) at 0 ºC under argon was added TBAF (1.1
equiv). The reaction mixture was allowed to warm to room temperature and stirred for 45 min. The
reaction was quenched with ice and brine. After extraction with Et2O, the combined extracts were
dried (MgSO4), concentrated, and chromatographed on silica gel (75:25 Hex-EtOAc) yielding 56 mg
(90%) of 14 as a colorless oil; 1H-NMR (CDCl3) δ 7.37-7.16 (m, 10H), 4.97 (d, J = 6.7 Hz; 1H), 4.66
(d, J =6.7 Hz, 1H), 4.33 (c, J = 11.7 Hz, 2H), 4.10 (d, J = 14.2 Hz, 1H), 3.85-3.80 (m, 1H), 3.73 (d, J =
14.2 Hz, 1H), 3.43-3.40 (m, 3H), 3.40 (s, 3H), 2.98-2.86 (m, 2H), 2.59 (t, J = 10.2 Hz, 1H), 2.17 (m,
13
1H), 2.08 (d, J = 12.2 Hz, 1H), 1.80-1.77 (m, 3H), 1.62-1.49 (m, 2H), 1.30-1.20 (m, 2H); C-NMR
(CDCl3) δ 208.6 (s), 140.4 (s), 138.3 (s), 128.2 (d), 127.5 (d), 127.4 (d), 126.9 (d), 97.0 (t), 73.2 (d),
72.7 (t), 67.2 (t), 60.1 (d), 57.8 (d), 57.5 (d), 55.5 (q), 51.6 (t), 43.2 (t), 32.2 (t), 30.7 (t), 30.6 (t), 21.8
(t); EIMS m/z (%): 437 (M+, 0.7); HRMS (EI): C27H35NO4 (M+): 437.2566, found 437.2554.
Acknowledgements
This work was supported in part by Grant BQU2001-3184 (MEC, Spain) and a University of La
Laguna Grant for Consolidated Research Groups.
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Sample Availability: Samples of the compounds described in this paper are available from authors.
© 2007 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.