Synthesis of enantiopure highly substituted trans-8a- hydroxydecahydroisoquinolines by sequential diastereoselective IMDA reaction and oxanorbornene nucleophilic ring opening

Full text of DOI:10.1021/jo981075c

8570
J . Org. Chem. 1998, 63, 8570-8573
stituent at C-2, the highly regio- and stereoselective
Syn th esis of En a n tiop u r e High ly
Su bstitu ted
tr a n s-8a -Hyd r oxyd eca h yd r oisoqu in olin es
by Sequ en tia l Dia ster eoselective IMDA
Rea ction a n d Oxa n or bor n en e Nu cleop h ilic
Rin g Op en in g
oxanorbornene nucleophilic ring opening9 with triethyl-
aluminum, and the elimination of the chiral appendage.
Attempts to prepare 3 by condensation of 2-furaldehyde
with (-)-8-((3′-butenyl)amino)menthol (2), obtained by
alkylation of (-)-8-aminomenthol (1) with 4-bromo-1-
butene (K2CO3, toluene, reflux), under standard condi-
tions failed.8a However, the heating of a mixture of
2-furaldehyde and 2 for 9 days in toluene at reflux led to
3, which immediately cyclized in these conditions to the
diastereomeric exo adducts 4a ,b, isolated as a mixture
4:1 in 90% total yield. The stereoselectivity of the IMDA
reaction is highly increased (9:1 4a /4b) when the reaction
was carried out by heating a mixture of the reactants,
without solvent, at 160 °C for 4 days, although the
chemical yield decreased to 70%, probably as a conse-
quence of decomposition of starting material under those
somewhat harsh reaction conditions (Scheme 1). Flash
chromatography on silica gel using hexanes-EtOAc as
eluent allowed the isolation of the pure diastereoisomers
4a ,b as colorless solids.10
Celia Andre´s, J avier Nieto, Rafael Pedrosa,*,† and
Martina Vicente
Departamento de Quı´mica Orga´nica, Facultad de Ciencias,
Universidad de Valladolid, Dr. Mergelina s/ n,
47011-Valladolid, Spain
Received J une 5, 1998
The decahydroisoquinoline system, a component of
more than 500 alkaloids,1 has attracted a lot of synthetic
interest. Some of the synthetic approaches are the
hydrogenation of isoquinoline derivatives,2 reductive
cyclizations of disubstituted cyclohexanes,3 and intramo-
lecular Mannich reaction or related processes.4 Never-
theless, the most efficient and stereoselective method to
prepare saturated isoquinolines is the intramolecular
Diels-Alder reaction of 1,3,9-trienes with a nitrogen at
a suitable position.5
The predominance of the diastereomer 4a is a result
of the thermodynamic conditions used in the cyclization
reaction, and it is in accord with the results obtained in
the formation of isoindoline derivatives.6a
In previous work,6 we have shown that the chiral
perhydrobenzoxazines, derived from (-)-8-aminomenthol
(1), was a useful chirality inductor in asymmetric trans-
formations. This heterocycle 3, bearing a furan ring at
C-2 as diene and a 3-butenyl substituent at the nitrogen
atom as dienophile, would serve as a nitrogen source and
chiral inductor in the stereoselective synthesis of enan-
tiopure decahydroisoquinolines. The initial key step of
our approach is an intramolecular Diels-Alder reaction,
directed to assemble the bicyclic structure.7 Other
important transformations are the stereoselective ring
opening of the cyclic N,O-acetal8 to introduce the sub-
Reduction of 4a ,b with 1.5 equiv of aluminum hydride
(prepared from LAH and AlCl3) in THF at -10 °C for 15
min furnished the amino alcohols 5a ,b, respectively,
which upon oxidation with PCC in CH2Cl2 at room
temperature and treatment with 2.5 M solution of KOH
in THF-methanol afforded the enantiomeric epoxyiso-
quinoline derivatives 6a and ent-6a in excellent chemical
yields (Scheme 2). Otherwise, the treatment of the
cycloadducts 4a ,b with 3 equiv of AlH3 at room temper-
ature for 6 h led to the amino diols 7a ,b (92% total yield),
respectively, resulting from the ring opening of the N,O-
cyclic acetal moiety and the regio- and stereoselective
reduction of the oxanorbornene system.9 The mild reduc-
tion conditions contrast with those previously reported
for the reaction of related oxanorbornenes with DIBAL-
H.11 These amino diols were transformed into the
enantiopure trans-8a-hydroxydecahydroisoquinolines 9a
and ent-9a by sequential hydrogenation (PtO2/H2, etha-
nol, room temperature, 24 h) to 8a ,b and elimination of
the menthol appendage as described for 5a ,b (Scheme
2).
The stepwise reductive ring opening described opens
the possibility to introduce different substituents at C-1
and C-8 in the final isoquinolines regio- and stereoselec-
tively by a careful control of the reaction conditions. In
fact, the adduct 4a reacted with 4 equiv of trimethyla-
luminum in toluene, at room temperature, for 15 min
leading to the open epoxy amino alcohol 10 as a single
stereoisomer in 80% yield. This compound was trans-
formed into the enantiopure epoxy isoquinoline 11 by the
oxidation-elimination protocol described above.
† E-mail: pedrosa@wamba.cpd.uva.es.
(1) Southon, I. W., Buckingham, J ., Eds. Dictionary of Alkaloids;
Chapman and Hall: New York, 1989.
(2) Claret, P. A. In Comprehensive Organic Chemistry; Sammes, P.
G., Ed.; Pergamon: Oxford, U.K., 1979; Vol. 4, p 205.
(3) J ones, G. In Comprehensive Heterocyclic Chemistry; Boulton, J .,
Mckillop, A., Eds.; Pergamon: Oxford, U.K., 1984; Vol. 2, p 395.
(4) Overman, L. E.; Ricca, D. J . In Comprehensive Organic Synthesis;
Heathcock, C. H., Ed.; Pergamon: Oxford, U.K., 1991; Vol. 2, p 1007.
(5) (a) Ciganek, E. J . Am. Chem. Soc. 1981, 103, 6261. (b) Martin,
S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J . Org. Chem. 1983,
48, 5170. (c) Wattanasin, S.; Kathawala, F. G.; Boeckman, R. K., J r.
J . Org. Chem. 1985, 50, 3810. (d) Yamaguchi, R.; Otsuji, A.; Utimoto,
K. J . Am. Chem. Soc. 1988, 110, 2186. (e) Gutierrez, A. J .; Shea, K. J .;
Svoboda, J . J . J . Org. Chem. 1989, 54, 4, 4335. (f) Martin, S. F.; Benage,
B.; Geraci, L. S.; Hunter, J . E.; Mortimore, M. J . Am. Chem. Soc. 1991,
113, 6161. (g) Handa, S.; J ones, K.; Newton, C. G. J . Chem. Soc., Perkin
Trans. 1 1995, 1623. (h) Hudlicky, T.; Butora, G.; Fearnley, S. P.; Gum,
A. G.; Persichini, P. J ., III; Stabile, M. R.; Merola, J . S. J . Chem. Soc.,
Perkin Trans. 1 1995, 2393.
(6) (a) Andre´s, C.; Maestro, G.; Nieto, J .; Pedrosa, R.; Garc´ıa-Granda,
S.; Pe´rez-Carren˜o, E. Tetrahedron Lett. 1997, 38, 1463. (b) Andre´s, C.;
Duque-Soladana, J . P.; Iglesias, J . M.; Pedrosa, R. Synlett 1997, 1391.
(7) For examples of asymmetric IMDA reactions, see: (a) Mu-
kaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 29. (b) J ung, M. E.; Street,
L. J . Heterocycles 1988, 27, 45. (c) Prajapati, D.; Borthakur, D. R.;
Sandhu J . S. J . Chem. Soc., Perkin Trans. 1 1993, 1197. (d) Zylber, J .;
Tubul, A.; Brun, P. Tetrahedron: Asymmetry 1995, 6, 377. (e) Woo,
S.; Keay, B. A. Tetrahedron: Asymmetry 1994, 5, 1411.
(9) For a recent review on oxanorbornene ring opening see: Woo,
S.; Keay, B. A. Synthesis 1996, 669.
(10) All the described compounds were fully characterized by their
physical, analytical, and spectral data. The absolute configuration was
determined on the basis of the known configuration of the perhy-
drobenzoxazine moiety by COSY and NOESY experiments.
(11) Lautens, M.; Chiu, P.; Colucci, J . T. Angew. Chem., Int. Ed.
Engl. 1993, 32, 281.
(8) (a) Alberola, A.; Alvarez, M. A.; Andre´s, C.; Gonza´lez, A.; Pedrosa,
R. Synthesis 1990, 153. (b) Alberola, A.; Alvarez, M. A.; Andre´s, C.;
Gonza´lez, A.; Pedrosa, R. Synth. Commun. 1990, 20, 1149. (c) Alberola,
A.; Andre´s, C.; Pedrosa, R. Synlett 1990, 763.
10.1021/jo981075c CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/28/1998

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8571
Sch em e 1
Sch em e 3
Sch em e 2
occurred by the oxygen face in the perhydrobenzoxazine
by a synchronous retentive alkylation process, as previ-
ously noted for related systems.12
The compound 10 was subjected to the reaction with
an excess (8 equiv) of triethylaluminum in toluene for
20 h, at room temperature, leading to a mixture (4:1) of
the regioisomers 12 and 13 in 75% combined yield
(Scheme 3). It is worthy to note that, although the exo
SN2′ ring opening of the oxanorbornene system occurs
with total stereoselectivity by the â face of the double
bond as described for related oxatricyclo derivatives,13,8e
the regiochemistry was just the contrary.14 To our
knowledge, this is the first case where the nucleophilic
attack yields the open compound 12 with the OH at the
angular carbon as major regioisomer with good selectiv-
ity. As previously reported for alkoxy derivatives, elec-
trostatic repulsions or changes in the LUMO coefficients
caused by the nitrogen substituent could be responsible
for the change in the observed regioselectivity.15
Compound 12 was isolated from the reaction mixture
by flash chromatography (silica gel, 30:1 CHCl3/EtOH)
and subjected to hydrogenation (PtO2, 1 atm, EtOH, room
temperature, 24 h) to 14, which, upon elimination of the
chiral appendage, led to the enantiopure (1S,4aR,8R,
8aR)-8-ethyl-1-methyl-8a-hydroxydecahydroisoquino-
line (15) in 62% yield from 12 (Scheme 3).
In summary, a concise diastereoselective synthesis of
enantiopure decahydroisoquinolines has been achieved
in five steps from easily accessible (-)-8-aminomenthol.
(12) Andre´s, C.; Nieto, J .; Pedrosa, R.; Villaman˜a´n, N. J . Org. Chem.
1996, 61, 4130.
(13) Woo, S.; Keay, B. A. Tetrahedron Lett. 1992, 33, 7451.
(14) Lautens, M.; Chiu, P. Tetrahedron Lett. 1993, 34, 773.
(15) Arjona, O.; Ferna´ndez de la Pradilla, R.; Mart´ın-Domenech, A.;
Plumet, J . J . Org. Chem. 1989, 54, 4158.
The configuration of the newly created stereocenter
was determined as S by NOESY experiments, showing
that the nucleophilic ring opening of the N,O-acetal

8572 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
separated by filtration, and the residue was washed with EtOAc.
The organic layer was dried over anhydrous MgSO4, the solvent
was eliminated on Rotavapor, and the residue was purified by
flash chromatography on silica gel using EtOAc as eluent.
The described protocol allows to prepare a variety of
enantiopure isoquinoline derivatives with four stereo-
centers, three of which are contiguous, and with known
absolute configuration. The method opens a way to the
stereocontrolled synthesis of potentially important bio-
logically active molecules.
Am in o Alcoh ol 5a . Yield: 80%, colorless solid. Mp: 113-
114 °C (from hexane). [R]25 ) -6.40 (c ) 1.16, CH2Cl2). 1H
D
NMR (δ): 7.81 (s, 1H); 6.34 (dd, J 1 ) 5.7 Hz, J 2 ) 1.7 Hz, 1H);
5.99 (d, J ) 5.7 Hz, 1H); 4.99 (dd, J 1 ) 4.4 Hz, J 2 ) 1.7 Hz, 1H);
3.75 (d, J ) 12.9 Hz, 1H); 3.58 (dt, J 1 ) 10.3 Hz, J 2 ) 4.2 Hz,
1H); 3.14 (m, 1H); 2.71 (d, J ) 12.9 Hz, 1H); 2.29 (m, 1H); 1.97-
1.87 (m, 2H); 1.75-1.30 (m, 8H); 1.18 (s, 3H); 1.10-0.90 (m, 4H);
0.95 (s, 3H); 0.87 (d, 3H, J ) 6.5 Hz). 13C NMR (δ): 137.5; 135.9;
85.5; 79.3; 72.2; 60.2; 48.0; 46.4; 45.0; 44.6; 35.1; 34.3; 34.0; 32.6;
30.9; 26.0; 22.1; 21.6; 18.5. IR (Nujol): 3020 cm-1. MS (CI) (m/
z, %): 307 (M+ + 2, 22); 306 (M+ + 1, 100); 192 (44); 152 (32).
Exp er im en ta l Section
All the reactions were carried out in anhydrous solvents,
under argon atmosphere and in oven-dried glassware. Products
were isolated by flash chromatography using 240-400 mesh
silica gel. Melting points were determined in capillary tubes
and are uncorrected. The 1H NMR (300 MHz) and 13C DEPT-
NMR (75 MHz) spectra were registered using TMS as internal
standard and CDCl3 as solvent. Optical rotations were mea-
sured in a 1 dm cell, and concentrations are given in g/100 mL.
Mass spectra were recorded by electronic impact or chemical
ionization.
Am in o Alcoh ol 5b. Yield: 76%, colorless solid. Mp: 130-
131 °C (from pentane). [R]25 ) -16.89 (c ) 1.1, CH2Cl2). 1H
D
NMR (δ): 8.12 (s, 1H); 6.35 (dd, J 1 ) 5.8 Hz, J 2 ) 1.7 Hz, 1H);
5.98 (d, J ) 5.8 Hz, 1H); 4.91 (dd, J 1 ) 4.3 Hz, J 2 ) 1.7 Hz, 1H);
3.59 (d, J ) 12.5 Hz, 1H); 3.57 (dt, J 1 ) 10.2 Hz, J 2 ) 4.0 Hz,
1H); 3.21 (m, 1H); 2.80 (d, J ) 12.5 Hz, 1H); 2.10 (m, 1H); 1.96-
1.89 (m, 2H); 1.74-1.52 (m, 4H); 1.52-1.32(m, 4H); 1.16 (s, 3H);
1.05-0.90 (m, 3H); 0.93 (s, 3H); 0.89 (d, J ) 6.5 Hz, 3H). 13C
NMR (δ): 137.7; 135.7; 85.8; 78.9; 71.8; 60.0; 47.4; 47.0; 46.2;
44.6; 35.2; 34.6; 33.6; 31.4; 30.9; 25.8; 22.2; 20.9; 18.0. IR
Syn th esis of (-)-8-((3′-Bu ten yl)a m in o)m en th ol (2).
A
mixture of (-)-8-aminomenthol (17.1 g, 100 mmol), 4-bromo-1-
butene (11.16 mL, 110 mmol), and anhydrous K2CO3 (15.18 g,
110 mmol) in toluene (60 mL) was refluxed for 65 h. The
mixture was filtered, and the solid was washed with EtOAc. The
solvents were evaporated on a rotavapor, and the residue was
chromatographed on a column packed with silica gel and eluted
(Nujol): 3140 cm-1
.
MS (CI) (m/z, %): 307 (M+ + 2, 21); 306
(M+ + 1, 100); 304 (15); 192 (33).
with 1:8 EtOAc/hexane. Yield: 65%, colorless oil. [R]25
)
Syn th esis of Am in o Alcoh ols 7a ,b. To a mixture of LAH
(1.2 g, 31.6 mmol) and AlCl3 (1.4 g, 10.5 mmol) in THF (50 mL)
prepared as described above was added the adduct 4a or 4b (0.96
g, 3.17 mmol) in THF (20 mL). The mixture was heated to room
temperature, stirred for 6 h, and then cooled to 0 °C and
quenched by addition of a 15% solution of NaOH (50 mL). The
solids were filtered off and washed with EtOAc (4 × 30 mL),
and the organic layer was washed with brine and dried over
anhydrous Na2SO4. The solvents were eliminated on rotavapor,
and the residue was purified by flash chromatography (silica
gel, 1:25 EtOH-CHCl3).
D
-19.81 (c ) 1.0, CH2Cl2). 1H NMR (δ): 5.81-5.67 (m, 1H); 5.11-
5.02 (m, 2H,); 3.60 (dt, J 1 ) 10.2 Hz, J 2 ) 4.1 Hz, 1H); 2.73 (m,
1H); 2.62 (m, 1H); 2.19 (m, 2H); 1.93 (m, 1H); 1.70-1.60 (m, 2H);
1.42 (m, 1H); 1.26 (m, 1H); 1.10 (s, 3H); 1.09 (s, 3H); 0.90 (d, J
) 6.6 Hz, 3H). 13C NMR (δ): 135.2; 116.1; 71.8; 55.7; 48.8; 43.8;
39.2; 34.4; 33.9; 30.3; 25.5; 25.0; 21.5; 20.9. IR (film): 3150, 1625,
1190, 1050, 1020 cm-1
.
MS (CI) (m/z, %): 226 (M+ + 1, 100);
210 (11); 184 (34); 149 (15); 137 (33). Anal. Calcd for C14H27
-
NO: C, 74.6; H, 12.1; N, 6.2. Found: C, 74.3; H, 12.4; N, 5.8.
Syn th esis of Cycloa d d u cts 4a ,b. A mixture of amino
alcohol 2 (11.7 g, 52 mmol) and recently distilled furfural (13
mL, 157 mmol) was heated at 160 °C (oil bath) for 4 days. The
excess of aldehyde was distilled, and the oily residue was
subjected to flash chromatography (silica gel, 8:1, 5:1, 3:1 hexane/
EtOAc and pure EtOAc) to give, in order of elution, 4a and 4b.
Data for 4a (9.93 g, 63%) as a colorless solid; mp 102-103 °C
Am in o Alcoh ol 7a . Yield: 90%, colorless solid. Mp: 72-
74 °C (from pentane). [R]25 ) -15.95 (c ) 0.78, CH2Cl2). 1H
D
NMR (δ): 5.83 (ddd, J 1 ) 9.8 Hz, J 2 ) 4.2 Hz, J 3 ) 2.8 Hz, 1H);
5.62 (ddd, J 1 ) 9.8 Hz, J 2 ) 2.1 Hz, J 3 ) 1.9 Hz, 1H); 3.61 (dt,
J 1 ) 10.2 Hz, J 2 ) 4.0 Hz, 1H); 3.19 (m, 1H); 3.17 (d, J ) 11.5
Hz, 1H); 2.24 (m, 1H); 2.13 (m, 1H); 2.07 (d, J ) 11.5 Hz, 1H);
1.91 (m, 1H); 1.80-1.55 (m, 6H); 1.50-1.22 (m, 6H); 1.18 (s, 3H);
1.08-0.95 (m, 3H); 0.91 (s, 3H); 0.90 (d, J ) 6.5 Hz, 3H). 13C
NMR (δ): 131.5; 131.0; 72.8; 66.2; 60.8; 55.9; 46.4; 45.7; 44.3;
41.9; 35.0; 31.0; 28.0; 26.2; 25.9; 22.9; 22.1; 21.3; 18.6. IR
(Nujol): 3360, 1195 cm-1. MS (CI) (m/z, %): 309 (M+ + 2, 21);
308 (M+ + 1, 100); 306 (21); 290 (24); 194 (62).
(from pentane)) are as follows. [R]25 ) - 100.2 (c ) 1.0, CH2-
D
Cl2). 1H NMR (δ): 6.35 (d, J ) 5.8 Hz, 1H); 6.33 (dd, J 1 ) 1.5
Hz, J 2 ) 5.8 Hz, 1H); 5.13 (s, 1H); 4.93 (dd, J 1 ) 1.5 Hz, J 2
)
4.3 Hz, 1H); 3.58 (dt, J 1 ) 3.9 Hz, J 2 ) 10.5 Hz, 1H); 3.05 (dt, J 1
) 2.1 Hz, J 2 ) 11.3 Hz, 1H); 2.78 (dt, J 1 ) 3.5 Hz, J 2 ) 11.3 Hz,
1H); 1.97-1.88 (m, 2H); 1.75-1.65 (m, 3H); 1.65-1.45 (m, 7H);
1.24 (s, 3H); 1.17 (s, 3H); 1.12-0.94 (m, 1H); 0.94 (d, J ) 6.5
Hz, 3H). 13C NMR (δ): 136.4; 136.0; 86.2; 82.3; 78.9; 76.8; 55.6;
44.4; 41.3; 38.6; 35.0; 34.6; 31.7; 31.3; 30.6; 27.4; 25.1; 22.2; 21.6.
MS [m/z (%)]: 303 (3) (M+), 150 (18), 121 (17), 109 (76), 41 (100).
Anal. Calcd for C19H29NO2: C, 75.2; H, 9.6; N, 4.6. Found: C,
75.6; H, 9.3; N, 4.2.
Am in o Alcoh ol 7b. Yield: 91%, colorless oil. [R]25
)
D
+10.15 (c ) 0.7, CH2Cl2). 1H NMR (δ): 8.45 (broad s, 1H); 5.83
(ddd, J 1 ) 9.8 Hz, J 2 ) 4.0 Hz, J 3 ) 2.9 Hz, 1H); 5.59 (dt, J 1
)
9.8 Hz, J 2 ) 2.1 Hz, 1H); 3.61 (dt, J 1 ) 10.3 Hz, J 2 ) 4.0 Hz,
1H); 3.32 (m, 1H); 3.03 (dd, J 1 ) 11.0 Hz, J 2 ) 2.1 Hz, 1H); 2.22-
2.02 (m, 3H); 1.93 (m, 1H); 1.80-1.50 (m, 6H); 1.50-1.19 (m,
5H); 1.17 (s, 3H); 1.05-0.90 (m, 3H); 0.91 (s, 3H), 0.90 (d, J )
6.6 Hz, 3H). 13C NMR (δ): 131.9; 130.7; 71.8; 66.0; 62.0; 55.4;
46.8; 46.2; 44.5; 41.6; 35.0; 31.0; 26.9; 26.2; 26.0; 23.0; 22.1; 21.1;
19.1. IR (film): 3400, 1190, 1170 cm-1. MS (CI) (m/z, %): 309
(M+ + 2, 21); 308 (M+ + 1, 100); 306 (17); 290 (20); 194 (27).
Data for 4b (1.10 g, 7%, colorless solid; mp 119-120 °C (from
pentane)) are as follows. [R]25 ) + 24.1 (c ) 1.0, CH2Cl2). 1H
D
NMR (δ): 6.32 (dd, J 1 ) 1.7 Hz, J 2 ) 5.7, Hz, 1H); 6.12 (d, J )
5.7 Hz, 1H); 5.00 (dd, J 1 ) 1.7 Hz, J 2 ) 4.4 Hz, 1H); 4.53 (s,
1H); 3.43 (dt, J ) 4.3 Hz, 10.5 Hz, 1H); 2.99 (dt, J 1 ) 3.3 Hz, J 2
) 12.0 Hz, 1H); 2.18 (dt, J 1 ) 1.8 Hz, J 2 ) 12.0 Hz, 1H); 1.95
(m, 1H); 1.85 (m, 1H); 1.75-1.35 (m, 9H); 1.25-1.15 (m, 1H);
1.18 (s, 3H); 1.05-0.95 (m, 1H); 0.94 (s, 3H); 0.90 (d, J ) 6.5
Hz, 3H). 13C NMR (δ): 136.2; 135.6; 86.8; 85.4; 78.8; 74.7; 55.6;
49.0; 42.3; 41.0; 35.7; 34.3; 34.1; 31.1; 30.8; 25.5; 24.7; 21.7; 10.6.
MS [m/z (%)]: 303 (4) (M+), 288 (41), 150 (10), 121 (17), 109 (24),
55 (100). Anal. Calcd for C19H29NO2: C, 75.2; H, 9.6; N, 4.6.
Found: C, 75.5; H, 9.9; N, 4.3.
Red u ction of 7a ,b to Am in o Alcoh ols 8a ,b. A mixture of
the corresponding amino alcohol (0.6 g) and a spatula of PtO2
in ethanol (20 mL) was stirred for 24 h under H2 atmosphere at
room temperature. The catalyst was separated by filtration over
a pad of Celite, the solvent was eliminated on rotavapor, and
the residue was flash chromatographed on silica gel using 1:10
EtOH-HCCl3 as eluent.
Am in o Alcoh ol 8a . Yield: 90%, colorless oil. [R]25
)
D
Red u ction of 4a ,b to th e Am in o Alcoh ols 5a ,b. To a
suspension of LAH (0.60 g, 15.8 mmol) in dry THF (40 mL) at
-10 °C was added AlCl3 (0.70 g, 5.25 mmol) in small portions.
The mixture was stirred for 10 min, a solution of the adduct 4a
or 4b (0.96 g, 3.17 mmol) in THF (20 mL) was slowly dropped,
and then the mixture was stirred for 15 min. The reaction
mixture was quenched by addition of H2O (4 mL), the solid was
+24.81 (c ) 1.6, CH2Cl2). 1H NMR (δ): 8.52 (broad s, 1H); 3.61
(dt, J 1 ) 10.3 Hz, J 2 ) 4.0 Hz, 1H); 3.17 (m, 1H); 3.05 (dd, J 1
)
11.8 Hz, J 2 ) 2.2 Hz, 1H); 2.21 (dt, J 1 ) 11.5 Hz, J 2 ) 2.9 Hz,
1H); 2.00 (d, J ) 11.8 Hz, 1H); 1.90 (m, 1H); 1.80-1.55 (m, 8H);
1.55-0.90 (m, 11H); 1.18 (s, 3H); 0.91 (s, 3H); 0.90 (d, J ) 6.5
Hz, 3H). 13C NMR (δ): 72.9; 68.4; 61.0; 57.5; 46.3, 45.7; 44.0;
43.3; 36.8; 34.9; 30.9; 28.7; 27.0; 26.0; 25.8; 22.0; 21.0; 20.8; 18.5.

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8573
IR (film): 3240, 1190, 1170 cm-1. MS (CI) (m/z, %): 311 (M+
2, 23); 310 (M+ + 1, 100); 308 (30); 196 (66).
+
)
basic solution was extracted with CHCl3 (4 × 15 mL), and the
organic layer was dried over anhydrous MgSO4. After elimina-
tion of the solvent, the residue was purified by flash chroma-
tography (silica gel, 1:10 EtOH-CHCl3).
Am in o Alcoh ol 8b. Yield: 87%, colorless oil. [R]25
D
-36.78 (c ) 2.1, CH2Cl2). 1H NMR (δ): 8.37 (broad s, 1H); 3.60
(dt, J 1 ) 10.2 Hz, J 2 ) 4.1 Hz, 1H); 3.28 (m, 1H); 2.86 (dd, J 1
)
(4a S,6R,8a S)-6,8a -E p oxy-4a ,5,6,8-t et r a h yd r oisoq u in o-
11.2 Hz, J 2 ) 2.0 Hz, 1H); 2.07 (dt, J 1 ) 11.7 Hz, J 2 ) 2.4 Hz,
1H); 2.04 (d, J ) 11.2 Hz, 1H); 1.95 (m, 2H); 1.78-1.45 (m, 9H);
1.45-1.10 (m, 6H); 1.14 (s, 3H); 1.10-0.90 (m, 3H); 0.91 (d, J )
6.5 Hz, 3H); 0.90 (s, 3H). 13C NMR (δ): 72.0; 68.5; 60.3; 57.0;
46.5, 46.2; 44.3; 43.2; 36.3; 34.9; 30.8; 27.8; 27.0; 25.9; 25.8; 22.0;
21.1; 20.8; 18.3. IR (film): 3220, 1010, 980 cm-1. MS (CI) (m/z,
%): 311 (M+ + 2, 23); 310 (M+ + 1, 100); 308 (29); 196 (44).
Syn th esis of Am in o Alcoh ol 10. To a solution of 4a (0.76
g, 2.5 mmol) in toluene (30 mL) was slowly added a 2 M solution
(5 mL, 10 mmol) of trimethylaluminum in toluene, and the
mixture was stirred at room temperature for 15 min. The
solution was quenched by addition of a mixture of saturated
solution of ammonium chloride and ice and the solid separated
by filtration and washed with EtOAc. The organic layer was
washed with brine and dried over anhydrous Na2SO4. The
solvents were evaporated on a rotavapor, and the residue was
flash chromatographed on silica gel, using a mixture of 1:20
EtOH-CHCl3 as eluent. Yield: 80%, colorless solid. Mp: 90-
lin e (6a ). Yield: 83%, colorless oil. [R]25 ) + 27.96 (c ) 1.0,
D
CH2Cl2). 1H NMR (δ): 6.38 (dd, J 1 ) 5.7 Hz, J 2 ) 1.6 Hz, 1H);
5.94 (d, J ) 5.7 Hz, 1H); 4.95 (dd, J 1 ) 4.4 Hz, J 2 ) 1.6 Hz, 1H);
3.53 (d, J ) 14.7 Hz, 1H); 3.27 (d, J ) 14.7 Hz, 1H); 3.05 (m,
1H); 2.61 (dt, J 1 ) 13.2 Hz, J 2 ) 2.3 Hz, 1H); 2.39 (broad s, 1H);
1.91 (m, 1H); 1.62 (m, 1H); 1.53 (dd, J 1 ) 11.0 Hz, J 2 ) 7.2 Hz,
1H); 1.44 (ddd, J 1 ) 11.0 Hz, J 2 ) 4.4 Hz, J 3 ) 2.8 Hz, 1H); 1.34
(m, 1H). 13C NMR (δ): 137.6; 135.6; 84.0; 79.0; 48.1; 45.6; 35.1;
33.5; 33.0. IR (film): 3320, 1315 cm-1. Anal. Calcd for C9H13
NO: C, 71.5; H, 8.7; N, 9.3. Found: C, 71.9; H, 9.0; N, 9.7.
-
(4a R,6S,8a R)-6,8a -E p oxy-4a ,5,6,8-t et r a h yd r oisoq u in o-
lin e (en t-6a ). Yield: 80%, colorless oil. [R]25 ) -28.22 (c )
D
0.98, CH2Cl2). Anal. Calcd for C9H13NO: C, 71.5; H, 8.7; N,
9.3. Found: C, 71.5; H, 9.1; N, 9.2.
(4a R,8a R)-8a -Hyd r oxyd eca h yd r oisoqu in olin e (9a ). Yield:
66%, colorless oil. [R]25D ) +29.74 (c ) 1.27, CH2Cl2). 1H NMR
(δ): 3.45 (broad s, 2H); 3.05-2.95 (m, 1H); 2.69 (d, J ) 11.5 Hz,
1H); 2.60 (dt, J 1 ) 11.9 Hz, J 2 ) 3.0 Hz, 1H); 2.42 (d, J ) 11.5
Hz, 1H); 1.74-1.12 (m, 11H). 13C NMR (δ): 67.9; 57.6; 46.6;
42.7; 35.6; 28.2; 28.0; 26.1; 21.2. IR (film): 3320, 1610, 1445
cm-1. MS (CI) (m/z, %): 157 (M+ + 2, 45); 156 (M+ + 1, 100);
155 (M+, 38). Anal. Calcd for C9H17NO: C, 69.6; H, 11.0; N,
9.0. Found: C, 70.0; H, 10.6; N, 9.3.
91 °C (from pentane). [R]25 ) -28.02 (c ) 1.1, CH2Cl2). 1H
D
NMR (δ): 8.46 (broad s, 1H); 6.30 (dd, J 1 ) 5.8 Hz, J 2 ) 1.6 Hz,
1H); 6.20 (d, J ) 5.8 Hz, 1H); 4.89 (dd, J 1 ) 4.6 Hz, J 2 ) 1.6 Hz,
1H); 3.71 (q, J ) 6.7 Hz, 1H); 3.67 (dt, J 1 ) 10.4 Hz, J 2 ) 4.2
Hz, 1H); 2.98-2.86 (m, 2H); 2.04-1.89 (m, 2H); 1.83-1.50 (m,
6H); 1.50-1.37 (m, 2H); 1.38 (d, J ) 6.7 Hz, 3H), 1.24 (s, 3H);
1.10-0.88 (m, 3H); 1.05 (s, 3H); 0.91 (d, J ) 6.5 Hz, 3H). 13C
NMR (δ): 137.2; 136.3; 90.1; 77.4; 72.6; 61.3; 48.2; 47.2; 44.1;
44.0; 36.7; 36.0; 35.5; 31.2; 29.4; 26.2; 22.3; 22.1; 22.0; 20.5. IR
(Nujol): 3090, 1050, 935 cm-1. MS (CI) (m/z, %): 321 (M+ + 2,
23); 320 (M+ + 1, 100); 206 (64); 166 (67).
(4a S,8a S)-8a -Hyd r oxyd eca h yd r oisoqu in olin e (en t-9a ).
Yield: 55%, colorless oil. [R]25 ) -28.17 (c ) 0.65, CH2Cl2).
D
Anal. Calcd for C9H17NO: C, 69.6; H, 11.0; N, 9.0. Found: C,
69.9; H, 11.4; N, 9.2.
Syn th esis of Am in o Alcoh ol 12. To a solution of 10 (1 g,
3.13 mmol) in toluene (50 mL) was added a 2 M solution (12.5
mL, 25 mmol) of triethylaluminum in toluene. The mixture was
stirred at room temperature for 20 h and manipulated as
(1S,4a S,6R,8a S)-1-Met h yl-6,8a -ep oxy-4a ,5,6,8-t et r a h y-
d r oisoqu in olin e (11). Yield: 80%, colorless oil. [R]25
)
D
+15.08 (c ) 1.1, CH2Cl2). 1H NMR (δ): 6.42 (dd, J 1 ) 5.8 Hz,
J 2 ) 1.6 Hz, 1H); 6.07 (d, J ) 5.8 Hz, 1H); 4.94 (dd, J 1 ) 4.5 Hz,
J 2 ) 1.6 Hz, 1H); 3.53 (q, J ) 7.2 Hz, 1H); 3.49 (broad s, 1H);
described for the preparation of 10 to yield a colorless oil. [R]25
D
) - 82.38 (c ) 1.0, CH2Cl2). 1H NMR (δ): 5.80 (ddd, J 1 ) 9.9
2.96-2.77 (m, 2H); 1.87 (m, 1H); 1.76 (m, 1H), 1.53 (dd, J 1
)
Hz, J 2 ) 4.8 Hz, J 3 ) 0.6 Hz, 1H); 5.51 (dd, J 1 ) 9.9 Hz, J 2
)
11.2 Hz, J 2 ) 7.1 Hz, 1H); 1.46 (d, J ) 7.2 Hz, 3H); 1.43 (m,
1H); 1.39 (m, 1H). 13C NMR (δ): 138.4; 134.4; 87.4; 78.6; 49.3;
38.5; 35.7; 32.4; 30.3; 17.1. IR (film): 3320, 1140 cm-1. Anal.
Calcd for C10H15NO: C, 72.7; H, 9.1; N, 8.5. Found: C, 72.9; H,
9.4; N, 8.7.
1.3 Hz, 1H); 4.20 (broad s, 2H); 3.56 (dt, J 1 ) 10.3 Hz, J 2 ) 3.9
Hz, 1H); 3.39 (q, J ) 6.6 Hz, 1H); 2.83 (m, 1H); 2.75 (m, 1H);
2.02 (m, 1H); 1.92 (m, 1H); 1.86-1.50 (m, 6H); 1.50-1.15 (m,
6H); 1.21 (s, 3H); 1.11 (s, 3H); 1.05-0.90 (m, 2H); 1.01 (d, J )
6.6 Hz, 3H); 0.94 (t, J ) 7.3 Hz, 3H); 0.90 (d, J ) 6.6 Hz, 3H).
13C NMR (δ): 135.2; 131.2; 72.8; 70.6; 59.9; 56.7; 49.9; 45.3; 38.9;
36.4; 35.3; 31.4; 30.5; 28.4; 27.9; 27.2; 26.8; 24.4; 23.9; 22.1; 12.5;
11.1. IR (film): 3320, 1185, 965 cm-1. MS (CI) (m/z, %): 351
(M+ + 2, 23); 350 (M+ + 1, 100); 348 (52); 332 (22).
(1S,4a R,8R,8a R)-1-Met h yl-8-et h yl-8a -h yd r oxyd eca h y-
d r oisoqu in olin e (15). Yield: 62%, colorless oil. [R]25D ) -3.38
(c ) 0.68, CH2Cl2). 1H NMR (δ): 3.02 (broad s, 2H); 2.91 (dt, J 1
) 12.2 Hz, J 2 ) 3.2 Hz, 1H); 2.74 (q, J ) 7.0 Hz, 1H); 2.67 (ddd,
J 1 ) 12.2 Hz, J 2 ) 5.5 Hz, J 3 ) 1.5 Hz, 1H); 1.70 (m, 1H); 1.71-
1.17 (m, 11H); 1.17 (d, J ) 7.0 Hz, 3H); 0.88 (t, J ) 7.4 Hz, 3H).
13C NMR (δ): 71.1; 57.6; 38.8; 34.6; 31.9; 30.1; 28.9; 28.7; 24.5;
23.8; 10.0; 12.6. IR (film): 3280, 1440, 1100 cm-1. MS (CI) (m/
z, %): 199 (M+ + 2, 19); 198 (M+ + 1, 100); 197 (M+, 17); 180
(82). Anal. Calcd for C12H23NO: C, 73.1; H, 11.7; N, 7.1.
Found: C, 72.8; H, 11.4; N, 6.8.
Am in o Alcoh ol 14. Compound 14 was obtained by hydro-
genation of 12 as described for 8a ,b. Yield: 98%, colorless oil.
[R]25 ) +1.06 (c ) 1.9, CH2Cl2). 1H NMR (δ): 5.33 (broad s,
D
2H); 3.99 (q, J ) 6.7 Hz, 1H); 3.57 (dt, J 1 ) 10.4 Hz, J 2 ) 4.0
Hz, 1H); 3.27 (m, 1H); 3.12 (m, 1H); 2.10-1.88 (m, 4H); 1.80-
1.20 (m, 13H); 1.45 (s, 3H); 1.30 (d, J ) 6.7 Hz, 3H); 1.29 (s,
3H); 1.10-0.90 (m, 3H); 0.93, (d, J ) 6.5 Hz, 3H); 0.87 (t, J )
7.2 Hz, 3H). 13C NMR (δ): 72.6; 72.2; 68.5; 61.9; 46.7; 42.6; 40.6;
34.1; 34.0; 31.6; 30.5; 29.3; 27.7; 27.1; 26.5; 23.7; 23.6; 22.9; 22.8;
21.5; 12.4; 10.3. IR (film): 3200, 1140 cm-1. MS (CI) (m/z, %):
353 (M+ + 2, 19); 352 (M+ + 1, 77); 350 (35); 238 (100); 198 (34).
E lim in a t ion of t h e Men t h ol Ap p en d a ge. Gen er a l
Meth od . A mixture of the corresponding amino alcohol (1.65
mmol), PCC (1.41 g., 6.56 mmol), and 4 Å molecular sieves (1 g)
in CH2Cl2 was stirred at room temperature for 6 h. The mixture
was filtered through a pad of Celite, the solvent was eliminated,
and the residue was redissolved in 15% aqueous solution of
NaOH with the aqueous phase was extracted with Et2O (5 × 20
mL). The organics were washed with brine and dried over
anhydrous MgSO4. After elimination of the solvent and pyridine
under vacuum, the residue was redissolved in a mixture of THF
(8 mL), MeOH (4 mL), and a 2.5 M solution of KOH (4 mL) and
stirred at room temperature for 5 h. After elimination of the
THF and MeOH under vacuum, the aqueous residue was
acidified to pH ) 2 by addition of a 10% solution of HCl. The
aqueous phase was washed with Et2O (4 × 10 mL) and then
basified to pH ) 12 by addition of 15% solution of NaOH. The
Ack n ow led gm en t. We thank the Spanish DGICYT
(Project PB95-707) for the financial support of this work.
The predoctoral fellowship provided by the Spanish
Ministerio de Educacio´n y Ciencia (FPU Program) for
J .N. is also acknowledged.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra for compounds 4a ,b, 5a ,b, 6a , 7a ,b, 8a ,b,
9a , 10-12, 14, and 15, as well as COSY, NOESY, and
heteronuclear correlation experiments for 4a ,b, 6a , and 11 (42
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O981075C