Diels-Alder reactions of phenylglycinol-derived bicyclic lactams. Enantiodivergent synthesis of cis-hydroisoquinolines

Article abstract of DOI:10.1016/S0957-4166(03)00368-9

The diastereomeric phenylglycinol-derived unsaturated δ-lactams trans-3 and cis-3 react with dienes with exo facial diastereoselectivity to give the corresponding tricyclic adducts, which were ultimately converted to enantiomeric cis-hydroisoquinolines.

Full text of DOI:10.1016/S0957-4166(03)00368-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2033–2039
Diels–Alder reactions of phenylglycinol-derived bicyclic lactams.
Enantiodivergent synthesis of cis-hydroisoquinolines
Nu´ria Casamitjana,a Mercedes Amat,a Nu´ria Llor,a Marc¸al Carreras,a Xavier Pujol,a
M. Montserrat Ferna´ndez,a Virgina Lo´pez,a Elies Molins,b Carles Miravitllesb and Joan Boscha,*
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
bInstitut de Cie`ncia de Materials (CSIC), Campus UAB, 08193 Cerdanyola, Spain
Received 4 April 2003; accepted 1 May 2003
Abstract—The diastereomeric phenylglycinol-derived unsaturated d-lactams trans-3 and cis-3 react with dienes with exo facial
diastereoselectivity to give the corresponding tricyclic adducts, which were ultimately converted to enantiomeric cis-hydroiso-
quinolines. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Many bioactive natural and synthetic products incorpo-
rate a totally (or partially) reduced isoquinoline ring
system. Among them, of particular interest are the
indole alkaloids of the yohimbine-reserpine type,1
which display a variety of therapeutic effects, and man-
zamines, a family of marine sponge metabolites that
exhibit antitumor and antibiotic activity.2
Previous work from lactams trans-3 and cis-3, and
related unsaturated d-lactams, has revealed that under
kinetic control they undergo conjugate addition reac-
tions with high exo facial diastereoselectivity, the
configuration of the new stereocenter generated in the
process being determined by the configuration of the
methine 8a carbon.5a,b,e
Although the Diels–Alder reaction between 5,6-dihy-
dro-2-pyridones and appropriate dienophiles has been
extensively used to construct the functionalized cis-
hydroisoquinoline skeleton in the racemic series, mainly
in the context of the synthesis of manzamines,3 the
enantioselective version of the process has been little
explored.4
To study the stereochemical outcome of Diels–Alder
cycloadditions we initially selected lactams trans-3 and
cis-3, which were prepared from the corresponding
saturated lactams trans-1 and cis-1 via the respective
selenides trans-2 and cis-2 as previously reported.5a
Diels–Alder reactions on trans-3 using 2,3-dimethyl-
1,3-butadiene 4a and 2-methyl-1,3-butadiene 4b as
dienes were carried out either under high-pressure con-
ditions (Method A) or using Lewis acid catalysis
(Method B). In both cases the process was highly
stereoselective as only the exo diastereomers, 5a and 5b,
respectively, were isolated (Scheme 1). The absolute
configuration of adduct 5a was unambiguously proven
by X-ray crystallography.8 A similar facial diastereose-
lectivity was observed from the more activated diene 4c
under high pressure conditions. The resulting cycload-
duct 5c was isolated in 64% yield as a 3:1 epimeric
mixture at C-6 and converted either to ketone 6 (one
stereoisomer of absolute configuration at C-6 not deter-
mined) by treatment with TBAF or to enone 7 by
treatment with 10% HF in acetonitrile (Scheme 2).
In the context of our studies on the enantioselective
synthesis of piperidine-containing derivatives from
phenylglycinol-derived d-lactams,5,6 we report here an
enantiodivergent synthetic entry to cis-hydroisoquinoli-
nes, the key step being an intermolecular Diels–Alder
reaction on a bicyclic 5,6-dihydro-2-pyridone.
Related asymmetric Diels–Alder cycloadditions on
L-
valinol-derived unsaturated g-lactams have been
employed to provide isoindole-1-one cycloadducts with
an excellent facial diastereoselectivity.7
* Corresponding author. Tel.: +34 93 4024538; fax: +34 93 4024539;
e-mail: jbosch@farmacia.far.ub.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00368-9

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N. Casamitjana et al. / Tetrahedron: Asymmetry 14 (2003) 2033–2039
absolute configuration was unambiguously confirmed
by X-ray diffraction techniques8 (Scheme 4). In this
case minor amounts of the endo isomer were also
isolated. In the presence of a Lewis acid catalyst the
reaction led to hydroisoquinolone 11% (the C-10a epimer
of 11) as the major product, a result that can be
rationalized by considering that the initially formed
cycloadduct 11 undergoes equilibration to the more
stable 3,10a-trans isomer. A similar equilibration under
acidic conditions from lactam cis-1 to trans-1 has been
reported.5a
To compare the stereochemical outcome of the Diels–
Alder reactions on lactams trans-3 and cis-3, tricyclic
adducts 5a and 11 were treated with alane (AlCl3/
LiAlH4), which caused the cleavage of the CꢀO bond of
the oxazolidine ring and the simultaneous reduction of
the ester and lactam carbonyl groups to give alcohols
12 and 14, respectively (Scheme 5). In agreement with
the proposed stereochemistry for the minor stereoiso-
mers isolated in the Diels–Alder reactions from cis-3, a
similar alane reduction from the endo isomer of 11 led
Scheme 1. Reagents and conditions: (i) LHMDS, ClCO2Me,
PhSeBr, THF, −78°C; (ii) O3, CH2Cl2, −78°C, then O2, 25°C;
(iii) 4, CH2Cl2, 12 kbar, or ZnBr2, CH2Cl2.
Scheme 2. Reagents and conditions: (i) TBAF, THF, 3 h; (ii)
10% HF, MeCN, 2 h.
The same exo diastereoselectivity was observed in the
Diels–Alder reaction between the 3,8a-trans unsatu-
rated lactam 9 and butadiene 4a (Scheme 3). This
lactam, bearing a phenylsulfonyl instead of a methoxy-
carbonyl activating group, was prepared from trans-1
via dithioacetal 8 and used without further purification
because of its tendency to give the corresponding 2-
pyridone.
Scheme 4. Reagents and conditions: (i) LHMDS, ClCO2Me,
PhSeBr, THF, −78°C; (ii) O3, CH2Cl2, −78°C, then O2, 25°C;
(iii) 2,3-dimethyl-1,3-butadiene 4a, CH2Cl2, 12 kbar, 18 h, rt
or ZnBr2, CH2Cl2, 5 h, rt.
Scheme 3. Reagents and conditions: (i) LHMDS, S-phenyl
benzene thiosulfonate, THF, −78°C; (ii) aq. NaHCO3, then
m-CPBA, CH2Cl2; (iii) 2,3-dimethyl-1,3-butadiene 4a,
CH2Cl2, 12 kbar, 22 h, rt.
We then studied the behavior of unsaturated lactam
cis-3 as dienophile in the Diels–Alder reaction with
butadiene 4a. Under high pressure conditions the exo
adduct 11 was formed as the major product, whose
Scheme 5. Reagents and conditions: (i) AlCl3, LiAlH4, THF,
−78 to 25°C; (ii) di-tert-butyl dicarbonate, EtOAc, Pd(OH)2/
C, H2, 24 h, rt.

N. Casamitjana et al. / Tetrahedron: Asymmetry 14 (2003) 2033–2039
2035
to 12 (50%), whereas the 10a epimer 11% gave 14 (56%).
3. Experimental
Finally, removal of the chiral substituent on the pipe-
ridine nitrogen from the above diastereomeric cis-
hydroisoquinolines 12 and 14 by hydrogenolysis in the
presence of di-tert-butyl dicarbonate provided 13 and
ent-13, respectively.
3.1. General
Melting points were determined in a capillary tube and
are uncorrected. Unless otherwise indicated, NMR
spectra were recorded at 300 MHz (1H) and 75 MHz
(13C), and chemical shifts are reported in l values
downfield from TMS. Only noteworthy IR absorptions
are listed. Thin-layer chromatography was done on
SiO2 (silica gel 60 F254), and the spots were located with
aqueous potassium permanganate solution or with
iodoplatinate reagent. Flash chromatography was car-
ried out using SiO2 (silica gel 60, SDS, 35–70 m). All
nonaqueous reactions were performed under an inert
atmosphere. Solvents for chromatography were distilled
at atmospheric pressure prior to use and dried using
standard procedures. Drying of the organic extracts
during the workup of reactions was performed over
anhydrous Na2SO4 or MgSO4. Evaporation of solvents
was accomplished with a rotatory evaporator. Micro-
analyses and HMRS were performed by Centre d’In-
vestigacio´ i Desenvolupament (CSIC), Barcelona.
In conclusion, as in the kinetically controlled conjugate
additions to related unsaturated d-lactams reported pre-
viously,5a,b,e the approach of the diene in the cycloaddi-
tions here studied occurs stereoselectively from the
convex face of the bicyclic lactam, syn with respect to
the 8a methine proton.
In summary, we have developed an enantiodivergent
synthetic entry to cis-hydroisoquinolines. Starting from
a single isomer of phenylglycinol it is possible to gain
access to the two enantiomeric series of cis-hydroiso-
quinolines by simply using either the kinetic bicyclic
lactam cis-1, formed in the cyclodehydration of (R)-
phenylglycinol with methyl 5-oxopentanoate, or the
most stable isomer trans-1. Diels–Alder reactions on
the respective a,b-unsaturated lactams cis-3 and trans-3
provide enantiopure diastereomeric cis-hydroisoquino-
lines, which are ultimately converted to the correspond-
ing separate enantiomers (Scheme 6).
3.2. (3R,5aR,9aS,10aS)-5a-(Methoxycarbonyl)-7,8-
dimethyl-5-oxo-3-phenyl-2,3,9,9a,10,10a-hexahydro-6H-
oxazolo[3,2-b]isoquinoline 5a
A stream of ozone gas was bubbled through a cooled
(−78°C) solution of the selenide trans-25a (345 mg, 0.80
mmol) in anhydrous CH2Cl2 (20 mL) until it turned
pale blue (ca. 30 min). The solution was purged with O2
for 20 min, and the temperature was slowly raised to
25°C. After 30 min of stirring, the mixture was poured
into brine (10 mL), and the aqueous layer was extracted
with CH2Cl2. The combined organic extracts were dried
and concentrated under reduced pressure (external tem-
perature 25°C) to give the unsaturated lactam trans-3
as an oil (348 mg), which was used in the next reaction
without further purification.
Method A. A mixture of crude unsaturated lactam
trans-3 (120 mg), obtained from selenide trans-2 (118
mg, 0.27 mmol) operating as above, and 2,3-dimethyl-
1,3-butadiene 4a (150 mL, 1.37 mmol) in anhydrous
CH2Cl2 (4 mL) was allowed to react under a pressure of
12 kbar for 12 h at rt. The mixture was diluted with
CH2Cl2, washed with brine, dried, and concentrated to
give, after flash column chromatography (75:25 hex-
ane–EtOAc), pure compound 5a (59 mg, 61% from
1
trans-2). IR (film) 1743, 1663 cm−1; H NMR (CDCl3)
l 1.63 (s, 3H), 1.65 (s, 3H), 1.83 (d, J=17.7 Hz, 1H),
2.06 (ddd, J=14.7, 5.0, 3.5 Hz, 1H), 2.16 (ddd, J=14.7,
10.0, 6.0 Hz, 1H), 2.24 (masked, 1H), 2.31 (d, J=18.0
Hz, 1H), 2.70–2.84 (m, 2H), 3.74 (s, 3H), 3.76 (dd,
J=8.7, 7.5 Hz, 1H), 4.49 (app t, J=8.4 Hz, 1H), 4.99
(dd, J=5.7, 3.6 Hz, 1H), 5.38 (app t, J=7.8 Hz, 1H),
7.18–7.40 (m, 5H); 13C NMR (CDCl3) l 18.7 (CH3),
18.9 (CH3), 28.8 (CH2), 30.0 (CH), 33.6 (CH2), 33.8
(CH2), 52.5 (CH3), 54.5 (C), 58.1 (CH), 71.5 (CH2),
85.8 (CH), 122.9 (C), 123.0 (C), 125.7 (2 CH), 127.4
(CH), 128.7 (2 CH), 139.6 (C), 169.9 (C), 172.0 (C); MS
[EI, m/z (%)] 355 (M+, 15), 296 (90), 91 (100), 77 (54);
Scheme 6.

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N. Casamitjana et al. / Tetrahedron: Asymmetry 14 (2003) 2033–2039
[h]2D2 −13.0(c1.15, CHCl3). Anal. calcdforC21H25NO4·1/4
H2O: C, 70.08; H, 7.14; N, 3.89. Found: C, 70.30; H, 7.02;
N, 3.88.
1-methoxy-3-(triisopropylsilyloxy)-1,3-butadiene 4c (500
mg, 1.94 mmol) in anhydrous CH2Cl2 (5 mL) was allowed
to react under a pressure of 12 kbar for 24 h at rt. The
mixture was diluted with CH2Cl2, washed with brine,
dried, and concentrated. Flash chromatography (4:1
hexane–EtOAc) of the residue gave the two C-6 epimers
of 5c (146 mg, 49%; 45 mg, 15%). Major epimer: IR (film)
1745, 1662 cm−1; 1H NMR (CDCl3) l 1.09 (cs, 18 H), 1.15
(m, 3H), 1.97 (d, J=17.7 Hz, 1H); 2.08 (dd, J=14.5, 6.5
Hz, 1H), 2.35 (ddm, J=17.7, 6.6 Hz, 1H), 2.61 (ddd,
J=14.5, 14.5, 7.0 Hz, 1H), 3.00 (m, 1H), 3.29 (s, 3H),
3.72 (m, 3H), 3.74 (dd, J=8.7, 7.2 Hz, 1H), 4.50 (app t,
J=8.4 Hz, 1H), 4.61 (d, J=5.1 Hz, 1H), 4.94 (d, J=6.3
Hz, 1H), 5.19 (dd, J=5.5, 1.0 Hz, 1H), 5.32 (app t, J=7.5
Hz, 1H), 7.20–7.38 (m, 5H); 13C NMR (CDCl3) l 12.5
(3 CH), 17.8 (6 CH3), 28.6 (CH), 28.7 (CH2), 32.4 (CH2),
52.5 (CH3), 57.2 (CH), 57.4 (C), 58.3 (CH3), 71.7 (CH2),
75.5 (CH), 86.0 (CH), 100.1 (CH), 125.7 (2 CH), 127.2
(CH), 128.5 (2 CH), 139.8 (C), 151.8 (C), 166.9 (C), 169.8
(C). Minor epimer: IR (film) 1737, 1669 cm−1; 1H NMR
(CDCl3) l 1.06 (cs, 18H), 1.18 (m, 3H), 2.16 (dd, J=18.0,
9.0 Hz, 1H), 2.31 (m, 2H), 2.52 (ddd, J=10.0, 8.5, 1.5
Hz, 1H), 3.20 (m, 1H), 3.26 (s, 3H), 3.74 (dd, J=9.0, 7.5
Hz, 1H), 3.77 (s, 3H), 4.52 (app t, J=8.4 Hz, 1H), 4.67
(d, J=6.0 Hz, 1H), 5.05 (dd, J=8.4, 6.0 Hz, 1H), 5.12
(d, J=6.0 Hz, 1H), 5.25 (app t, J=7.8 Hz, 1H), 7.10–7.35
(m, 5H); 13C NMR (CDCl3) l 12.6 (3 CH), 17.9 (6 CH3),
28.3(CH), 29.8(CH2), 31.5(CH2), 52.9(CH3), 56.2 (CH3),
57.4 (C), 58.5 (CH), 72.8 (CH2), 77.2 (CH), 86.0 (CH),
99.2 (CH), 125.6 (2 CH), 127.4 (CH), 128.7 (2 CH), 139.4
(C), 154.3 (C), 163.6 (C), 169.4 (C).
Method B. A solution of the above crude unsaturated
lactam trans-3 in anhydrous CH2Cl2 (15 mL) was added
to a suspension of anhydrous ZnBr2 (197 mg, 0.87 mmol)
in CH2Cl2 (5 mL). Then, an excess of 2,3-dimethyl-1,3-
butadiene 4a (0.5 mL, 4.42 mmol) was added dropwise,
and the mixture was stirred under argon at rt for 4 h 30
min. The mixture was washed with brine, and the aqueous
layer was extracted with CH2Cl2. The combined organic
extracts were dried and concentrated, and the resulting
oil was chromatographed (3:1 hexane–EtOAc) to give
pure compound 5a (184 mg, 65% from trans-2).
3.3. (3R,5aR,9aS,10aS)-5a-(Methoxycarbonyl)-8-
methyl-5-oxo-3-phenyl-2,3,9,9a,10,10a-hexahydro-6H-
oxazolo-[3,2-b]isoquinoline 5b
MethodA. Amixtureofcrudeunsaturatedlactam trans-3,
obtained from selenide trans-2 (250 mg, 0.58 mmol)
operating as above, and 2-methyl-1,3-butadiene 4b (0.29
mL, 2.90 mmol) in anhydrous CH2Cl2 (3 mL) was allowed
to react under a pressure of 12 kbar for 24 h at rt. The
mixture was diluted with CH2Cl2, washed with brine,
dried, and concentrated to give, after flash column
chromatography (8:2 hexane–EtOAc), compound 5b (79
1
mg, 40% from trans-2). IR (film) 1747, 1665 cm−1; H
NMR (CDCl3) l 1.67 (s, 3H), 1.82 (d, J=17.7 Hz, 1H),
2.09 (ddd, J=14.7, 5.7, 2.7 Hz, 1H), 2.19 (ddd, J=14.7,
10.8, 6.2 Hz, 1H), 2.22 (masked, 1H), 2.35 (dm, J=17.8,
Hz, 1H), 2.83–2.96 (m, 2H), 3.75 (s, 3H), 3.77 (dd, J=9.0,
7.4 Hz, 1H), 4.49 (app t, J=8.2 Hz, 1H), 5.00 (dd, J=6.3,
2.7 Hz, 1H), 5.37–5.43 (m, 2H), 7.18–7.36 (m, 5H); 13C
NMR (CDCl3) l 23.5 (CH3), 27.5 (CH2), 28.3 (CH2), 29.4
(CH), 32.0 (CH2), 52.5 (CH3), 53.5 (C), 58.1 (CH), 71.4
(CH2), 85.7 (CH), 117.6 (CH), 125.7 (2 CH), 127.4 (CH),
128.7 (2 CH), 131.1 (C), 139.6 (C), 170.3 (C), 171.7 (C);
MS [EI, m/z (%)] 341 (M+, 9), 310 (10), 282 (88), 91 (100),
77 (62); [h]2D2 −15.3 (c 1.08, CHCl3). Anal. calcd for
C20H23NO4·3/2 H2O: C, 66.01; H, 7.06; N, 3.85. Found:
C, 65.67; H, 6.67; N, 3.61.
3.5. (3R,5aS,9aR,10aS)-6-Methoxy-5a-(methoxycar-
bonyl)-5,8-dioxo-3-phenyl-2,3,6,7,9,9a,10,10a-octahydro-
8H-oxazolo[3,2-b]isoquinoline 6
TBAF (100 mg, 0.32 mmol) was added to a solution of
compound 5c (146 mg, 0.27 mmol, major epimer) in THF
(5 mL), and the mixture was stirred with an external
ice-bath for 3 h. A saturated aqueous NH4Cl solution was
added, and the mixture was extracted with CH2Cl2. The
combined organic extracts were dried and concentrated,
and the residue was chromatographed (3:2 hexane–
EtOAc) to give ketone 6 (92 mg, 89%) as a solid. IR (KBr)
1743, 1715, 1651 cm−1; 1H NMR (CDCl3) l 2.26–2.38 (m,
3H), 2.58–2.75 (m, 2H), 2.87 (dd, J=18.0, 3.8 Hz, 1H),
2.90 (dd, J=16.0, 14.0 Hz, 1H), 3.15 (s, 3H), 3.74 (dd,
J=9.0, 8.0 Hz, 1H), 3.76 (s, 3H), 4.41 (dd, J=3.8, 2.4
Hz, 1H), 4.57 (dd, J=9.0, 7.8 Hz, 1H), 5.13 (dd, J=7.8,
5.4 Hz, 1H), 5.33 (app t, J=8.0 Hz, 1H), 7.20–7.37 (m,
5H); 13C NMR (CDCl3) l 31.4 (CH2), 31.5 (CH), 40.6
(CH2), 42.0 (CH2), 53.0 (CH3), 56.7 (C), 58.1 (CH3), 59.1
(CH), 72.8 (CH2), 78.7 (CH), 85.3 (CH), 125.8 (2 CH),
127.5 (CH), 128.6 (2 CH), 138.7 (C), 164.5 (C), 171.2 (C),
208.1 (C); mp 101–103°C. Anal. calcd for C20H23NO6: C,
64.33; H, 6.21; N, 3.75. Found: C, 64.20; H, 6.37; N, 3.76.
Method B. Anhydrous ZnBr2 (259 mg, 1.15 mmol) and
2-methyl-1,3-butadiene 4b (575 mL, 5.75 mmol) were
added to a solution of crude unsaturated lactam trans-3,
obtained from selenide trans-2 (495 mg, 1.15 mmol)
operating as above, in anhydrous CH2Cl2 (5 mL). The
resulting mixture was stirred under argon at rt for 16 h
andthenpouredintobrine. Theaqueouslayerwaswashed
with EtOAc (10 mL) and CH2Cl2. The combined organic
extracts were dried and concentrated to give an oil, which
was chromatographed (3:1 hexane–EtOAc) to give pure
5b (165 mg, 42% from trans-2).
3.4. (3R,5aR,9aS,10aS)-6-Methoxy-6a-(methoxycar-
bonyl)-5-oxo-3-phenyl-8-(triisopropylsilyloxy)-
2,3,9,9a,10,10a-hexahydro-6H-oxazolo[3,2-b]isoquinoline
5c
A mixture of unsaturated lactam trans-3, obtained as
above from selenide trans-2 (239 mg, 0.55 mmol), and
3.6.
(3R,5aS,9aR,10aS)-5a-(Methoxycarbonyl)-5,8-
dioxo-3-phenyl-2,3,9,9a,10,10a-hexahydro-8H-oxazolo-
[3,2-b]isoquinoline 7
A solution of 10% HF in MeCN (4.4 mL) was added to
a solution of the crude Diels–Alder adduct 5c, obtained

N. Casamitjana et al. / Tetrahedron: Asymmetry 14 (2003) 2033–2039
2037
with CH2Cl2 (20 mL). The organic phase was washed
with aqueous NaHCO3, dried, and concentrated to
give sulfone 9. The crude mixture was dissolved in
CH2Cl2 (8 mL), 2,3-dimethyl-1,3-butadiene 4a (200
mL, 1.75 mmol) was added, and the mixture was
allowed to react under a pressure of 12 kbar for 22 h
at rt. The solvent was eliminated under reduced pres-
sure, and the residue was chromatographed (65:35
hexane–EtOAc) to give adduct 10 (87 mg, 40% from
8). IR (KBr) 1659, 1296, 1140 cm−1; 1H NMR
(CDCl3) l 1.45 (s, 3H), 1.61 (s, 3H), 2.18 (dd, J=
17.0, 8.0 Hz, 1H), 2.80 (m, 2H), 2.31 (ddd, J=13.5,
5.4, 3.0 Hz, 1H), 2.47 (dd, J=17.0, 8.5 Hz, 1H), 2.70
(ddd, J=13.5, 9.3, 4.2 Hz, 1H), 3.39 (m, 1H), 3.74
(dd, J=9.0, 7.8 Hz, 1H), 4.64 (dd, J=9.0, 8.4 Hz,
1H), 5.09 (dd, J=9.3, 5.4 Hz, 1H), 5.32 (app t, J=
8.0 Hz, 1H), 7.1 (m, 2H), 7.18–7.33 (m, 3H), 7.45–
7.55 (m, 2H),7.60 (m, 1H), 7.85–7.93 (m, 2H); 13C
NMR (CDCl3) l 18.5 (CH3), 18.9 (CH3), 29.9 (CH),
30.8 (CH2), 35.4 (CH2), 36.4 (CH2), 59.2 (CH), 71.5
(C), 73.2 (CH2), 86.5 (CH), 123.3 (C), 125.4 (2 CH),
125.7 (C), 127.5 (CH), 128.3 (2 CH), 128.8 (2 CH),
131.0 (2 CH), 133.7 (CH), 137.1 (C), 139.2 (C), 163.9
(C); mp 123–125°C; [h]2D2 −5.5 (c 0.3, EtOH). Anal.
calcd for C25H27NO4S: C, 68.63; H, 6.22; N, 3.20; S,
7.33. Found: C, 68.31; H, 6.39; N, 3.12; S, 6.98.
operating as above from selenide trans-2 (610 mg, 1.42
mmol), in MeCN (7 mL). The resulting mixture was
stirred for 2 h at rt. Saturated aqueous NaHCO3 was
added, and the mixture was diluted with CH2Cl2. The
layers were separated, and the aqueous phase was
extracted with additional CH2Cl2. The combined
organic extracts were dried and concentrated. Purifica-
tion of the residue by flash chromatography (35:65
hexane–EtOAc) afforded pure enone 7 (234 mg, 48%
from trans-2). IR (KBr) 1736, 1690, 1655 cm−1; 1H
NMR (400 MHz, CDCl3) l 2.25–2.39 (m, 2H), 2.55–
2.65 (m, 2H), 3.04 (m, 1H), 3.82 (s, 3H), 3.83 (dd,
J=9.0, 8.0 Hz, 1H), 4.60 (dd, J=9.0, 8.0 Hz, 1H), 5.15
(dd, J=8.4, 5.6 Hz, 1H), 5.33 (t, J=8.0 Hz, 1H), 6.19
(d, J=10.4 Hz, 1H), 7.12 (d, J=10.4 Hz, 1H), 7.20
(dm, J=8.4 Hz, 2H), 7.24–7.36 (m, 3H); 13C NMR
(100.6 MHz, CDCl3) l 29.4 (CH2), 34.1 (CH), 39.8
(CH2), 53.6 (CH3), 55.7 (C), 58.9 (CH), 72.8 (CH2),
86.1 (CH), 126.0 (2 CH), 128.0 (CH), 128.9 (2 CH),
129.4 (CH), 138.7 (C), 146.0 (CH), 163.9 (C), 170.6 (C),
195.8 (C); [h]2D2+3.1 (c 0.32, EtOH). HRMS calcd for
C19H19NO5 341.1263, found 341.1273.
3.7.
(3R,8aS)-5-Oxo-3-phenyl-6,6-bis(phenylsulfanyl)-
2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine 8
Lithium bis(trimethylsilyl)amide (9 mL, 1.0 M in
THF) was slowly added at −78°C to a solution of
lactam trans-1 (651 mg, 3.0 mmol) in anhydrous
THF (30 mL), and the resulting mixture was stirred
for 1 h. Then, a solution of S-phenyl benzenethiosul-
fonate (2.25 g, 9.0 mmol) in anhydrous THF (7.5
mL) was slowly added, and the mixture was stirred
for 90 min at −78°C, warmed to rt, and poured into
brine. The aqueous layer was extracted with EtOAc,
and the combined organic extracts were dried and
concentrated. Flash chromatography of the resulting
oil (7:3 hexane–EtOAc) afforded pure compound 8
3.9.
(3R,5aS,9aR,10aR)-5a-(Methoxycarbonyl)-7,8-
dimethyl-5-oxo-3-phenyl-2,3,9,9a,10,10a-hexahydro-6H-
oxazolo[3,2-b]isoquinoline 11
Method A. The unsaturated lactam cis-3 was prepared
from selenide cis-25a (350 mg, 0.81 mmol) following
the experimental procedure above described for the
preparation of trans-3. To a solution of the crude
mixture of cis-3 in CH2Cl2 (4 mL) was added 2,3-
dimethyl-1,3-butadiene 4a (320 ml, 2.83 mmol), and the
mixture was allowed to react under a pressure of 12
kbar for 18 h at rt. The solvent was eliminated under
reduced pressure, and the residue was purified by flash
column chromatography (3:2 hexane–EtOAc) afford-
ing isoquinoline 11 (118 mg, 40% from cis-2) and the
endo isomer (20 mg, 7%). Crystallization from Et2O–
hexane afforded pure 11: IR (KBr) 1745, 1659 cm−1;
1H NMR (400 MHz, CDCl3) l 1.61 (s, 3H), 1.64 (s,
3H), 1.95 (dd, J=17.2, 6.0 Hz, 1H), 2.13–2.21 (m,
2H), 2.25 (ddd, J=13.2, 7.6, 6.0 Hz, 1H), 2.44 (br s,
2H), 2.84 (app q, J=6.0 Hz, 1H), 3.55 (s, 3H), 4.05
(dd, J=9.0, 2.0 Hz, 1H), 4.18 (dd, J=9.0, 7.2 Hz,
1H), 4.84 (dd, J=7.2, 2.0 Hz, 1H), 5.01 (dd, J=7.6,
6.0 Hz, 1H), 7.20–7.25 (m, 5H); 13C NMR (100.6
MHz, CDCl3) l 18.7 (CH3), 18.9 (CH3), 30.2 (CH2),
32.2 (CH), 33.8 (CH2), 52.4 (CH3), 54.6 (C), 58.7
(CH), 74.2 (CH2), 86.3 (CH), 123.3 (C), 123.8 (C),
126.7 (2 CH), 127.6 (CH), 128.3 (2 CH), 140.7 (C),
166.7 (C), 172.6 (C); mp 227–230°C; MS [EI, m/z (%)]
355 (M+, 12), 296 (100), 133 (38), 91 (54). HRMS
calcd for C21H25NO4 355.1783, found 355.1782; [h]D22
−131.3 (c 0.6, MeOH). Anal. calcd for C21H25NO4 1/4
H2O: C, 70.08; H, 7.14; N, 3.89. Found: C, 70,17; H,
6.92; N, 3.77. endo Isomer of 11: IR (KBr) 1747, 1660
cm−1; 1H NMR (CDCl3) l 1.58 (s, 6H), 1.75–1.99
1
(1.1 g, 85%). IR (KBr) 1657 cm−1; H NMR (CDCl3)
l 1.88–1.95 (m, 2H), 1.98–2.10 (m, 2H), 3.74 (dd,
J=9.0, 8.1 Hz, 1H), 4.46 (dd, J=9.0, 7.8 Hz, 1H),
4.74 (dd, J=7.2, 6.3 Hz, 1H), 5.28 (app t, J=7.8 Hz,
1H), 7.10–7.20 (m, 4H), 7.25–7.45 (m, 9H), 7.74 (dm,
J=7.8 Hz, 2H); 13C NMR (CDCl3) l 25.1 (CH2),
28.3 (CH2), 59.1 (CH), 64.8 (C), 72.6 (CH2), 88.4
(CH), 126.8 (2 CH), 127.7 (CH), 128.6 (2 CH), 128.8
(2 CH), 129.2 (CH), 129.8 (CH), 129.9 (C), 131.4 (C),
136.3 (2 CH), 137.2 (2 CH), 138.8 (C), 166.2 (C); mp
144–146°C; [h]2D2 −49.0 (c 0.5, CHCl3). Anal. calcd for
C25H23NO2S2: C, 69.25; H, 5.35; N, 3.23; S, 14.79.
Found: C, 69.40; H, 5.38; N, 3.15; S, 14.78.
3.8.
(3R,5aR,9aS,10aS)-5a-(Benzenesulfonyl)-7,8-
dimethyl-5-oxo-3-phenyl-2,3,9,9a,10,10a-hexahydro-6H-
oxazolo[3,2-b]isoquinoline 10
Aqueous NaHCO3 (0.5 M, 5 mL) was added to a
solution of compound 8 (216 mg, 0.5 mmol) in
CH2Cl2 (5 mL). Then, m-CPBA (70% of purity, 370
mg, 1.5 mmol) was added in small portions. The
resulting mixture was stirred at rt for 3 h and diluted

2038
N. Casamitjana et al. / Tetrahedron: Asymmetry 14 (2003) 2033–2039
11.2, 1.2 Hz, 1H), 2.81 (d, J=10.8 Hz, 1H), 3.39 (d,
J=10.8 Hz, 1H), 3.39 (d, J=10.8 Hz, 1H), 3.62–3.75
(m, 2H), 3.98 (dd, J=10.0, 9.6 Hz, 1H), 7.19 (m,
2H), 7.28–7.37 (m, 3H); 13C NMR (100.6 MHz,
CDCl3) l 18.8 (CH3), 19.1 (CH3), 29.1 (CH2), 33.8
(CH), 35.0 (CH2), 37.5 (C), 52.2 (CH2), 52.9 (CH2),
60.4 (CH2), 68.5 (CH2), 70.2 (CH), 121.9 (C), 122.2
(C), 127.8 (CH), 128.2 (2 CH), 128.9 (2 CH), 135.6
(C); [h]2D2 −4.6 (c 0.2, MeOH). HRMS calcd for
C20H29NO2 315.2198, found 315.2186. Anal. calcd for
C20H29NO2·1/2H2O: C, 74.04; H, 9.32; N, 4.32.
Found: C, 73.63; H, 9.19; N, 4.14.
(m, 1H), 2.20 (dt, J=12.6, 3.6 Hz, 2H), 2.50 (d, J=
17.4 Hz, 1H), 2.72 (ddd, J=9.3, 6.3, 3.0 Hz, 1H),
3.69 (s, 3H), 4.07 (dd, J=9.3, 1.2 Hz, 1H), 4.18 (dd,
J=9.3, 6.9 Hz, 1H), 4.84 (dd, J=6.9, 1.2 Hz, 1H),
4.98 (dd, J=9.9, 4.2 Hz, 1H), 7.30–7.35 (m, 5H); 13C
NMR (CDCl3) l 18.4 (CH3), 18.8 (CH3), 31.5 (CH),
31.6 (CH2), 33.6 (CH2), 34.9 (CH2), 52.5 (CH3), 54.2
(C), 58.5 (CH), 73.8 (CH2), 87.9 (CH), 121.8 (C),
122.0 (C), 126.6 (2 CH), 127.6 (CH), 128.4 (2 CH),
140.7 (C), 166.9 (C), 171.9 (C); [h]2D2 +34.7 (c 0.76,
MeOH).
Method B. Anhydrous ZnBr2 (211 mg, 0.94 mmol)
and 2-methyl-1,3-butadiene 4b (500 mL, 4.45 mmol)
were added to a solution of crude unsaturated lactam
cis-3, obtained from selenide cis-2 (350 mg, 0.81
mmol) operating as above, in anhydrous CH2Cl2 (4
mL). The resulting mixture was stirred under argon
at rt for 5 h and then poured into brine. The
aqueous layer was washed with CH2Cl2, and the com-
bined organic extracts were dried and concentrated.
The resulting oil was chromatographed (3:2 hexane–
EtOAc) to give 11% (81 mg, 28% from cis-2) and 11
3.11. (4aS,8aR)-8a-(Hydroxymethyl)-2-[(1R)-2-hydroxy-
1-phenylethyl]-6,7-dimethyl-2,3,4,4a,5,8-hexahydro-
1H-isoquinoline 14
Operating as above described for 12, starting from
lactam 11 (300 mg, 0.84 mmol), pure compound 14
(170 mg, 64%) was obtained after flash chromatogra-
phy (EtOAc). IR (KBr) 3404 cm−1; 1H NMR (400
MHz, CDCl3) l 1.34–1.43 (m, 3H), 1.57 (s, 3H), 1.61
(s, 3H), 1.49–1.70 (m, 2H), 1.77 (tm, J=10.5 Hz,
1H), 2.18 (dm, J=17.6 Hz, 1H), 2.27 (d, J=11.2 Hz,
1H), 2.48 (d, J=17.2 Hz, 1H), 2.56 (d, J=11.2 Hz,
1H), 2.83 (dm, J=10.5 Hz, 1H), 3.37 (d, J=10.4 Hz,
1H), 3.43 (d, J=10.4 Hz, 1H), 3.61–3.72 (m, 2H),
4.01 (m, 1H), 7.19 (dm, J=8.0 Hz, 2H), 7.28–7.37
(m, 3H); 13C NMR (100.6 MHz, CDCl3) l 18.9
(CH3), 19.1 (CH3), 28.9 (CH2), 33.9 (CH), 33.9
(CH2), 35.0 (CH2), 38.1 (C), 46.2 (CH2), 58.7 (CH2),
60.5 (CH2), 68.4 (CH2), 69.9 (CH), 121.8 (C), 122.3
(C), 127.8 (CH), 128.2 (2 CH), 128.9 (2 CH), 135.6
(C); [h]2D2 −4.5 (c 0.25, MeOH). HRMS calcd for
C20H29NO2 315.2198, found 315.2194.
1
(9 mg, 3%). 11%: IR (KBr) 1749, 1650 cm−1; H NMR
(400 MHz, CDCl3) l 1.61 (s, 3H), 1.65 (s, 3H), 1.78–
1.84 (m, 2H), 2.18 (dd, J=5.6, 3.2 Hz, 1H), 2.22 (dd,
J=5.6, 3.2 Hz, 1H), 2.30 (d, J=18 Hz, 1H), 2.70–
2.75 (m, 2H), 3.73 (dd, J=8.8, 1.6 Hz, 1H), 3.72 (s,
3H), 4.51 (t, J=8.8 Hz, 1H), 5.08 (dd, J=7.6, 5.6
Hz, 1H), 5.23 (t, J=8.0 Hz, 1H), 7.22–7.35 (m, 5H);
13C NMR (100.6 MHz, CDCl3) l 18.4 (CH3), 18.9
(CH3), 30.9 (CH2), 31.3 (CH), 34.3 (CH2), 34.8
(CH2), 52.8 (CH3), 53.9 (C), 58.1 (CH), 72.6 (CH2),
87.5 (CH), 122.1 (C), 122.6 (C), 125.6 (2 CH), 127.5
(CH), 128.8 (2 CH), 139.3 (C), 168.0 (C), 172.0 (C);
mp 130–132°C; MS [EI, m/z (%)] 355 (M+, 21), 296
(100), 297 (22), 133 (29); [h]2D2 −2.2 (c 0.98, MeOH).
Anal. calcd for C21H25NO4·1/4H2O: C, 70.08; H, 7.14;
N, 3.89. Found: C, 69.97; H, 7.09; N, 3.98.
3.12. (4aR,8aS)-2-(tert-Butoxycarbonyl)-8a-(hydroxy-
methyl)-6,7-dimethyl-3,4,4a,5,8,8a-hexahydro-1H-iso-
quinoline 13
A solution of 12 (160 mg, 0.5 mmol) and di-tert-
butyl dicarbonate (218 mg, 1 mmol) in EtOAc (10
mL) containing 20% Pd(OH)2/C (32 mg) was hydro-
genated at rt for 24 h. The catalyst was removed by
filtration and washed with hot MeOH. The combined
organic solutions were concentrated, and the resulting
oil was chromatographed (8:2 EtOAc–hexane) afford-
ing pure compound 13 (105 mg, 71%) as a transpar-
3.10. (4aR,8aS)-8a-(Hydroxymethyl)-2-[(1R)-2-hydroxy-
1-phenylethyl]-6,7-dimethyl-2,3,4,4a,5,8-hexa-
hydro-1H-isoquinoline 12
LiAlH4 (256 mg, 6.75 mmol) was added to a suspen-
sion of AlCl3 (300 mg, 2.25 mmol) in anhydrous
THF (20 mL) at 0°C, and the mixture was stirred
under argon at 25°C for 30 min. The temperature
was lowered to −78°C, adduct 5a (268 mg, 0.75
mmol) in anhydrous THF (15 mL) was slowly added,
and the resulting suspension was stirred at rt for 24
h. The mixture was cooled to 0°C, and the reaction
was quenched with H2O. The aqueous layer was
extracted with CH2Cl2, and the combined organic
extracts were dried and concentrated. The residue was
chromatographed (35:65 hexane–EtOAc) to give pure
compound 12 (160 mg, 67%). IR (KBr) 3405 cm−1;
1H NMR (400 MHz, CDCl3) l 1.41 (m, 2H), 1.57 (s,
3H), 1.61 (s, 3H), 1.55–1.70 (m, 3H), 1.78 (d, J=11.2
Hz, 1H), 2.18 (d, J=17.6 Hz, 1H), 2.30 (td, J=10.8,
3.0 Hz, 1H), 2.40 (d, J=17.2 Hz, 1H), 2.59 (dd, J=
1
ent oil. IR (film) 3456, 1663 cm−1; H NMR (CDCl3)
l 1.37–1.41 (m, 2H), 1.46 (s, 9 H), 1.40–1.45 (m, 2H),
1.59 (s, 3H), 1.60 (s, 3H), 1.62–1.80 (m, 2H), 1.98 (br
d, J=17.7 Hz, 1H), 2.25 (d, J=18 Hz, 1H), 2.87 (d,
J=13.2 Hz, 2H), 3.36 (d, J=11.1 Hz, 1H), 3.53 (d,
J=11.1 Hz, 1H), 3.63 (dd, J=13.2, 1.2 Hz, 1H), 3.95
(br s, 1H); 13C NMR (CDCl3) l 18.8 (CH3), 19.0
(CH3), 28.0 (CH2), 28.5 (CH3), 33.3 (CH), 33.6 (CH),
35.1 (CH2), 38.0 (C), 43.4 (CH2), 49.3 (CH2), 67.4
(CH2), 79.4 (C), 122.1 (C), 122.3 (C), 155.5 (C); [h]D22
+5.0 (c 2.0, MeOH). Anal. calcd for C17H27NO.33/2
H2O: C, 63.72; H, 9.44; N, 4.37. Found: C: 63.76; H,
9.43; N, 4.29.

N. Casamitjana et al. / Tetrahedron: Asymmetry 14 (2003) 2039–2039
2039
3.13. (4aS,8aR)-2-(tert-Butoxycarbonyl)-8a-(hydroxy-
methyl)-6,7-dimethyl-3,4,4a,5,8,8a-hexahydro-1H-iso-
quinoline (ent-13)
2790; (f) Amat, M.; Canto´, M.; Llor, N.; Escolano, C.;
Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67,
5343–5351; (g) Amat, M.; Canto´, M.; Llor, N.; Ponzo, V.;
Pe´rez, M.; Bosch, J. Angew. Chem., Int. Ed. 2002, 41,
335–338; (h) Amat, M.; Llor, N.; Hidalgo, J.; Escolano,
C.; Bosch, J. J Org. Chem. 2003, 68, 1919–1928.
Operating as in the above preparation of 13, starting
from compound 14 (140 mg, 0.39 mmol), pure ent-13
(70 mg, 65%) was obtained. [h]2D2 −5.5 (c 2.0, MeOH).
6. For reviews on aminoalcohol-derived bicyclic lactams, see:
(a) Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997,
1–8; (b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000,
56, 9843–9873.
Acknowledgements
7. (a) Busacca, C. A.; Meyers, A. I. J. Chem. Soc., Perkin
Trans. 1 1991, 2299–2316. For other asymmetric Diels–
Alder cycloadditions on unsaturated g-lactams, see: (b)
Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org.
Chem. 1992, 57, 1059–1061; (c) Bailey, J. H.; Cherry, D.
T.; Crapnell, K. M.; Moloney, M. G.; Shim, S. B. Tetra-
hedron 1997, 53, 11731–11744.
8. The experiment was done on an Enraf–Nonius CAD4
diffractometer using graphite-monochromated Mo Ka
radiation. The structure was solved by direct methods
using SHELXS-97 [Sheldrick, G. M., 1997, SHELX-97.
Programs for Crystal Structure Analysis (Release 97-2),
University of Go¨ttingen, Germany] after applying Lorentz,
polarization, and absorption (semiempirical PSI scan
method) corrections. Full-matrix least squares refinement
(SHELXL-97) with anisotropic thermal parameters for
non-H atoms and riding thermal parameters for H-atoms
(positioned at calculated positions) converged to a R fac-
tor of 0.0815 (for 5a) and 0.0956 (for 11) (calculated for
the reflections with I>2|(I)). 5a: Crystal data: C21H25NO4,
monoclinic, space group P21, a=10.0358(15), b=
This work was supported by the DGICYT, Spain (pro-
ject BQU2000-0651). Thanks are also due to the
DURSI, Generalitat de Catalunya, for Grant
2001SGR-0084, the SCT of the University of Barcelona
for recording the NMR and MS spectra, and DSM
Deretil (Almer´ıa, Spain) for the generous gift of (R)-
phenylglycine.
References
1. Sza´ntay, C.; Honty, K. In Monoterpenoid Indole Alkaloids;
Saxton, J. E., Ed. In The Chemistry of Heterocyclic Com-
pounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994; Sup-
plement to Vol. 25, Part 4, Chapter 4.
2. For a review, see: Andersen, R. J.; Van Soest, R. W. M.;
Kong, F. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol.
10, pp. 301–355.
3. For reviews, see: (a) Nakagawa, M. J. Heterocyclic Chem.
2000, 37, 567–581; (b) Magnier, E.; Langlois, Y. Tetra-
hedron 1998, 54, 6201–6258. See also: (c) Gomez-Pardo,
D.; d’Angelo, J. Tetrahedron Lett. 1992, 33, 6637–6640.
4. (a) Uchida, H.; Nishida, A.; Nakagawa, M. Tetrahedron
Lett. 1999, 40, 113–116; (b) Casamitjana, N.; Lo´pez, V.;
Jorge, A.; Bosch, J.; Molins, E.; Roig, A. Tetrahedron
2000, 56, 4027–4042.
5. (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto´, M.; Pe´rez,
M.; Llor, N.; Molins, E.; Miravitlles, C.; Orozco, M.;
Luque, J. J. Org. Chem. 2000, 65, 3074–3084; (b) Amat,
M.; Pe´rez, M.; Llor, N.; Bosch, J.; Lago, E.; Molins, E.
Org. Lett. 2001, 3, 611–614; (c) Amat, M.; Llor, N.;
Huguet, M.; Molins, E.; Espinosa, E.; Bosch, J. Org. Lett.
2001, 3, 3257–3260; (d) Amat, M.; Canto´, M.; Llor, N.;
Bosch, J. Chem. Commun. 2002, 526–527; (e) Amat, M.;
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,
7.6157(15), c=12.502(2) A, i=95.490(16)°, V=951.1(3)
,
3
A , Z=2, v(Mo Ka)=0.086 mm−1, Dcalcd=1.241 g/cm3.
Approximate dimensions: 0.60×0.60×0.16 mm3. Data col-
lection was up to a resolution of 2q=60.8° producing 5732
unique reflections. Largest peak and hole at the final
−3
,
difference Fourier synthesis were 0.370 and −0.407 e A
.
CCDC deposition number 209021. 11: Crystal data:
C21H25NO4, monoclinic, space group P21, a=12.449(5),
,
b=6.844(11), c=22.832(14) A, i=104.19(5)°, V=1886(3)
,
3
A , Z=4, v(Mo Ka)=0.086 mm−1, Dcalcd=1.252 g/cm3.
Data collection was up to a resolution of 2q=60.1° pro-
ducing 5937 unique reflections. Largest peak and hole at
the final difference Fourier synthesis were 0.323 and
−0.372 e A−3. Calculations were done using the WinGX
,
package (Farrugia, L. J. J. Appl. Cryst. 1999, 32, 837–838).
CCDC deposition number 209022.