Diels-Alder reactions of 5,6-dihydro-2(1H)-pyridones

Article abstract of DOI:10.1016/S0040-4020(00)00317-3

The Diels-Alder reaction of achiral 5,6-dihydro-2(1H)-pyridones 12a,b and enantiopure 5,6-dihydro-2(1H)-pyridones 16a,b with a variety of diversely substituted buta-1,3-dienes under thermal or catalytic conditions, to give partially reduced isoquinolones 18-33 and 35-37, is reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00317-3

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4027±4042
Diels±Alder Reactions of 5,6-Dihydro-2(1H)-pyridones
a,
a
Nuria Casamitjana, Virginia Lopez, Angela Jorge, Joan Bosch, Elies Molins and Anna Roig
a
a,
b
b
*
*
Â
Â
aLaboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Á
Institut de Ciencia dels Materials de Barcelona (CSIC), Campus Universitari de Bellaterra, 08193 Cerdanyola, Spain
b
Received 16 December 1999; revised 27 March 2000; accepted 13 April 2000
AbstractÐThe Diels±Alder reaction of achiral 5,6-dihydro-2(1H)-pyridones 12a,b and enantiopure 5,6-dihydro-2(1H)-pyridones 16a,b
with a variety of diversely substituted buta-1,3-dienes under thermal or catalytic conditions, to give partially reduced isoquinolones 18±33
and 35±37, is reported. q 2000 Elsevier Science Ltd. All rights reserved.
The partially reduced isoquinoline moiety is present in a
large number of alkaloids belonging to different structural
types, most of them displaying notable pharmacological
activities.1 We present here a straightforward synthetic
entry to this structural unit, both in the racemic series and
in enantiopure form, that involves the Diels±Alder reaction
of 5,6-dihydro-2(1H)-pyridones as dienophiles with
diversely substituted buta-1,3-dienes 1±7 (see Table 1).2,3
vating benzyloxycarbonyl group is present at the pyridone
3 position.
The results of the Diels±Alder reactions between dihydro-
pyridones 10, 12 and 16 and dienes 1±7, under a variety of
experimental conditions, either thermal or with Lewis-acid
catalysis,5 are summarized in Table 1. The products
obtained are shown in Figs. 1±3. The stereochemical assign-
ment of the Diels±Alder adducts was effected from their
NMR data, with the aid of bidimensional (COSY and
HETCOR), 1H±1H decoupling, and NOE difference experi-
As the starting dihydropyridones we used 10a,b, 12a,b and
16a,b, which were prepared from 2-piperidone or (S)-5-hy-
droxy-2-piperidone (13),4 as outlined in Scheme 1. All of
these dihydropyridones bear an electron-withdrawing group
on the piperidine nitrogen atom in order to enhance the
reactivity of the carbon±carbon double bond as a dieno-
phile. In dihydropyridones 12 and 16 an additional acti-
1
ments, when necessary. Diagnostic H NMR data to deter-
mine the anti or syn stereochemistry in the chiral non-
racemic series were the J values of H-3, H-4 and H-4a of
the isoquinoline nucleus. Table 2 shows signi®cant 13C
NMR chemical shifts for the Diels±Alder adducts.
Scheme 1.
Keywords: Diels±Alder reaction; pyridones; isoquinolines.
* Corresponding authors. E-mail: casamitj@farmacia.far.ub.es
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00317-3

4028
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
Table 1. Diels±Alder reactions of 5,6-dihydro-2(1H)-pyridones
Table 1 (continued)
Conditionsa
Productsb (yield%)
Diene
Dienophile
Conditionsa
Productsb (yield%)
Diene
Dienophile
10a
12a
12a
Ac
Ac
Bc
17a (34)
18a (58)
18a (41)
19a (30)
18b (15)
19b (21)
18b (17)
19b (62)
20a (14)
22a (18)
20ad (40)
21a (13)
20ad (20)
20bd (29)
21b (11)
21b (28)
22b (19)
12a
12a
12b
16a
16b
A
C
C
C
C
29a (17)
29a (70)
29b (63)f
30ad (73)
30bd (67)
e
12b
12b
16a
16a
Ac
Bc
A
B
12a
12a
12b
12b
A
C
A
C
31a (38)
31a (51)
31b (9)
31b (32)
34b (14)
31b (67)
35ag (67)
38a (19)f
35b (46)
38b (10)
16a
16b
C
Bc
e
16b
C
12b
16a
D
C
12a
12b
16a
C
C
C
23a (65)
23b (67)
25a (18)
16b
C
27a (52)
25b127b (1:6, 82)
12a
12a
12b
A
C
A
32a (48)
32a (89)
32b (12)
32c (24)
32b (32)
34b (34)
36a (68)
16b
C
e
12a
12a
12b
12b
16a
A
C
A
C
C
24a (25)
24a (69)
24b (11)
24b (73)
26a (27)
12b
16a
C
C
12a
12a
Ac
C
33a (28)
33a (4)
28a (55)
26b128b (1:3, 75)
16b
C
34a (50)
33b (31)
34b (47)
37a (4)
12b
12b
16a
A
D
C
Thermal induced Diels±Alder reactions from 10 only
succeeded, although in moderate yield, using the N-tosyl-
dihydropyridone 10a and the highly reactive Danishefsky's
diene 16 in re¯uxing p-cymene. Treatment of the initially
formed adduct with camphorsulfonic acid brought about
both the hydrolysis of the silyl enol ether functionality
and elimination of methanol to give 17a (Fig. 1). When
using either 10b, a less reactive dienophile, or other dienes,
or solvents with a lower boiling point, the reactants were
recovered unchanged. The reaction of dienophiles 12a,b,
which incorporate an additional activating group at the 3
position, with diene 1 under thermal conditions proceeded
with higher yields to give the adducts 18 and 19, the latter
arising from elimination of methanol. It is worth mentioning
that when using benzene as the solvent the yield was higher,
probably because the starting dihydropyridones 12 decom-
pose at the p-cymene re¯ux temperature to give the less
reactive dihydropyridones 10 and their 3,6-dihydro isomers
(see Experimental). The elimination of methanol from the
initially formed 8-methoxy substituted adducts takes place
more easily from the exo diastereomers, in which the meth-
oxy group is in an axial disposition, than in the endo
isomers. In fact, attempts to perform this elimination from
endo-18a under acidic conditions (CSA or p-TsOH) were
unsuccessful.7 Diagnostic 13C NMR data for adducts endo-
18a and its C-8 epimer exo-18a are shown in Fig. 1. With
the enantiopure dihydropyridones 16a,b, Danishefsky's
diene reacted under both thermal and catalytic conditions
to afford adducts 20 (anti, minor amounts of other dia-
stereomers were also formed), 21 and 22 in moderate to
low yields.
38a (14)
a A: p-cymene, re¯ux. B: benzene, re¯ux. C: ZnBr2 or ZnCl2, CH2Cl2. D:
EtAlCl2, CH2Cl2.
b For the stereochemistry at C-5 and C-8, see Experimental.
c Followed by CSA treatment.
d Accompanied by a minor stereoisomer.
e Commercial mixture of isomers.
f Mixture of two diastereomers.
g Accompanied by two minor diastereomers.
with alkyl substituted buta-1,3-dienes 2 and 3 took place in
low yields under thermal conditions but in quite good yields
when using ZnBr2 or ZnCl2 as a catalyst to give the corre-
sponding adducts 23±28 (Fig. 2). With enantiopure dihydro-
pyridones 16a,b as the dienophiles, mixtures of
stereoisomeric adducts anti (25 and 26) and syn (27 and
28) were obtained, the latter being the major products.
Diagnostic H NMR data for these anti and syn adducts
are shown in Fig. 2. The absolute con®guration of 27a
was con®rmed by X-ray crystallography.
1
Similarly, cycloadditions of 12a,b and 16a,b with an E,Z
mixture of hexa-2,4-diene (4) in the presence of ZnBr2 as
catalyst afforded the respective adducts 29a,b and 30a,b in
good yields as mixtures of diastereomers of undetermined
con®guration at C-5 and C-8. As in the above alkyl sub-
stituted butadienes, the major diastereomers 30a,b formed
in the reaction of enantiopure dihydropyridones 16a,b
possessed a syn stereochemistry (J4±4a<5.5 Hz).
Dihydropyridones 12a,b and 16a,b were also allowed to
react with O-substituted 1-hydroxybuta-1,3-dienes 5 (Z/E
The Diels±Alder reaction of dienophiles 12a,b and 16a,b

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4029
Figure 1. Diels±Alder adducts from Danishefsky's diene and diagnostic 13C NMR data for adducts endo-18a and exo-18a.
Figure 2. Diels±Alder adducts from alkyl substituted buta-1,3-dienes and diagnostic 1H NMR data for adducts 25±28.
mixture), 6 (Z/E mixture), and 7 under a variety of reaction
conditions. The thermal cycloaddition reactions of 12a,b
with these dienes gave moderate yields of the corresponding
adducts 31a,b±33a,b as mixtures of endo/exo isomers (Fig.
3). Deprotection of the N-methoxycarbonyl substituent,
probably during puri®cation, occurred to some extent in
the reaction of diene 6 with dihydropyridone 12b to give
the N-unsubstituted bicyclic adduct 32c. The yields were
clearly higher when the reactions using dienes 5 and 6
were performed in the presence of a Lewis acid catalyst
(ZnCl2 or ZnBr2), although in series b aldehyde 34b, result-
ing from a Michael-type addition of the activated diene to
the conjugated C±C double bond of the dienophile, was also
formed. This problem was circumvented using EtAlCl2 as
the Lewis acid catalyst. Under these conditions dihydropyr-
idone 12b afforded adduct 31b (6:1 endo/exo mixture) in
67% yield as the only isolable product. However, the
Michael addition was the preponderant or exclusive pro-
cess when operating from the O-silyl diene 7, and no synth-
etically useful Diels±Alder reactions were produced with
this diene. In general, with O-substituted 1-hydroxybutadienes
the yields were slightly higher in the more reactive N-tosyl
Figure 3. Diels±Alder adducts from O-substituted 1-hydroxybuta-1,3-dienes.

4030
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
Table 2. Signi®cant 13C NMR chemical shifts of Diels±Alder adducts 17±37 (values with an asterisk are interchangeable)
C-3
C-4
C-4a
C-5
C-6
C-7
C-8
C-8a
Othera
17a
45.5
44.6
44.1
44.6
45.1
45.1
51.0
51.8
50.6
51.3
50.6
50.7
44.6
45.0
44.7
44.9
50.9
50.9
50.0
50.1
49.9
50.1
46.2
46.4
41.6
51.5
51.4
46.0
41.6
46.0
41.8
46.3
46.2
41.6
41.3
46.1
41.8
46.2
41.7
49.3
49.5
49.7
49.6
49.9
29.8
26.4
26.4
25.6
26.0
25.3
65.1
64.7
66.1
65.7
66.9
66.8
25.3
24.9
25.4
25.0
65.6
65.9
65.7
65.2
65.9
65.4
18.2
18.0
23.7
65.0
64.9
24.1
25.8
23.7
25.1
24.0
23.5
25.4
23.3
23.7
26.5
23.5
25.4
65.7
65.0
64.4
65.2
65.5
34.1
36.7
31.6
36.6
36.5
36.4
45.2
45.0
44.1
44.1
42.0
42.1
32.8
33.0
33.0
33.1
41.0
41.3
39.1
39.4
39.3
39.6
38.3
38.7
32.5
48.3
48.1
31.8
27.2
32.1
27.2
31.7
31.9
26.7
32.0
31.7
26.4
32.1
26.3
40.5
41.2
34.4
33.5
32.8
44.4
42.5
40.4
42.5
39.9
39.9
37.8
38.0
35.7
35.9
36.6
36.8
32.5
32.7
34.4
34.4p
27.5
29.5
26.5
26.4
28.1
28.1
28.9
32.5
34.0
30.9
30.9
27.5
30.2
27.7
30.2
27.7
27.8
30.7
28.1
27.6
30.9
27.8
30.5
22.3
22.4
22.5
22.2
22.2
206.2
207.2
206.2
-
40.0
41.4
42.1
41.3
130.6
130.3
42.0
136.8
82.7
80.6
82.6
143.9
144.4
83.4
83.4
144.0
144.7
144.0
144.6
28.8
29.0
34.4
34.6p
29.5
35.1
30.7
30.9
36.2
36.6
32.5
29.1
34.2
35.2
34.8.
66.9
67.0
67.5
67.6
74.9
74.9
73.8
74.3
65.9
66.2
66.5
66.4
70.8
71.6
67.6
73.7
66.2
131.5
59.0
60.3
59.6
±
endo-18a
exo-18a
18b
19a
19b
20a
20b
21a
21b
22a
22b
23a
23b
24a
24b
25a
26a
57.6
56.9
57.9,
200.0
195.4
206.4
206.9
194.6
195.0
194.9
195.4
130.8
130.8
121.9p
122.0p
130.7
122.4p
131.1
131.2
122.9p
122.8p
129.5
129.6
129.2
130.5p
130.2p
122.9
123.2
123.1
123.5
123.5
123.7
123.4
124.0
124.8
125.1
124.8
127.4
126.5p
126.9p
130.6
129.6
126.5p
58.3
59.2
60.0
58.0
58.8
56.5
57.2
55.3
55.9
56.5
57.0
54.6
55.7
54.6
55.2
55.6
56.2
59.5
60.3
59.7
59.9
61.0
59.5
59.0
59.3
59.5
59.7
60.4
60.6
57.7
60.2
61.5
60.7
61.5
58.6
59.3
58.6
59.7
60.7
57.6
57.8
41.9
131.2
131.1
131.0
130.8
116.9
117.1
122.6p
122.5p
117.3
122.5p
117.9
118.0
123.0p
123.0p
127.1
127.3
129.8
131.2p
131.4p
127.8
130.4
127.7
130.3
125.8
125.9
125.7
125.9
127.0
127.3
127.1
127.6
127.9p
127.7p
123.0
122.9
127.8p
23.2
23.4
18.4, 18.8
18.4, 18.8
23.2
18.4, 18.8,
23.1
23.2
18.4, 18.6
18.5, 18.7
17.6, 18.6
17.5, 19.1
17.5, 19.6
17.2, 18.2
17.5, 18.2
20.4,
20.6
20.9
20.6
58.6,
27a
27b
28a
28b
29a
29bb
29bc
30a
30b
endo-31a
exo-31a
endo-31b
exo-31b
endo-32a
endo-32b
exo-32b
endo-32c
endo-33a
exo-33a
endo-33b
exo-33b
endo-35a
endo-35b
exo-35b
exo-36a
endo-37a
58.8
57.0
59.1
-0.1
0.6
0.1
0.3
20.7
20.9
20.6
57.0
0.3
a Substituents on the carbocyclic ring.
b Less polar diastereomer.
c More polar diastereomer.
1
(a) series under both thermal conditions and with Lewis acid
catalysis.
adducts 31±33 and 35±37 was inferred from their H and
13C NMR spectra. Fig. 4 shows selected diagnostic NMR
data for these adducts. The 13C chemical shift of the ole®nic
6 and 7 carbons is of diagnostic value8 to establish the
pseudoequatorial or pseudoaxial disposition of the sub-
stituent at C-8 in adducts 35±37 derived from 16. The
con®guration of isoquinolone endo-35b was con®rmed by
X-ray crystallography.
Finally, taking into account the above results, Diels±Alder
reactions from the chiral non-racemic dienophiles 16a,b
were only studied in the presence of Lewis acids. Thus,
dienes 5 and 6 again gave satisfactory results, and the corre-
sponding adducts 35a,b and 36a,b were obtained in good
yields. In the former case, minor amounts of the respective
aldehydes 38a,b were also formed. As in the above racemic
series, diene 7 was not synthetically useful to obtain Diels±
Alder adducts.
In summary, the Diels±Alder reaction between 5,6-dihydro-
2(1H)-pyridones and substituted buta-1,3-dienes provides a
general entry to the partially reduced isoquinolone system,
both in the racemic series and in enantiopure form. Except
for the more reactive Danishefsky's diene, the best yields
are obtained when the cycloaddition is carried out using
Lewis acid catalysis. For each particular reaction the
highest yield is normally in the range 50±85%, although
in general both the endo/exo and syn/anti stereoselectivities
are low.
Concerning the syn/anti stereoselectivity with enantiopure
dienophiles 16a and 16b, it is worth mentioning that the
syn adducts 35, 36, and 37a,b were formed as the major
diastereomers, accompanied in some cases by minor
amounts of other diastereomers of undetermined con®gu-
ration. The endo/exo and syn/anti stereochemistry for

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4031
Figure 4. Diagnostic NMR data for adducts 31±33 and 35±37.
Experimental
55 (43). A solution of LHMDS (1 M in THF, 7.8 ml,
7.8 mmol) in anhydrous THF (40 ml) was slowly added
(30 min) under N2 to a solution of 8a (1.8 g, 7.08 mmol)
in anhydrous THF (40 ml) cooled at 2788C, and stirring
was continued at 2788C for 1 h. A solution of PhSeCl
(1.5 g, 7.8 mmol) in anhydrous THF (40 ml) was next
added, and the mixture was stirred at 08C for 30 min, poured
into H2O, and extracted with Et2O. The combined organic
extracts were washed with brine, dried, and concentrated to
give, after chromatography (¯ash, SiO2, 1:1 hexane±
AcOEt), 3-(phenylselanyl)-1-(p-toluenesulfonyl)-2-piper-
idone (9a) (1.7 g, 60%): mp 125±1278C (Et2O); IR (NaCl)
1683, 1349, 1168 cm21; 1H NMR (200 MHz) 1.74±2.23 (m,
4H, 4-H and 5-H), 2.45 (s, 3H, Me), 3.77±3.89 (m, 2H, 3-H
and 6-H), 3.94±4.06 (m, 1H, 6-H), 7.17±7.46 (m, 7H, Ph-H
and Ts-m-H), 7.92 (d, Jˆ8.4 Hz, 2H, Ts-o-H); 13C NMR
(50.3 MHz) 21.5 (C-5), 21.6 (Me), 28.0 (C-4), 43.5 (C-3),
46.4 (C-6), 127.7 (C-i-Ph), 128.6 (C-p-Ph), 128.8, 129.0 and
129.2 (C-Ph), 135.6 (C-p-Ts and C-o-Ph), 144.6 (C-i-Ts),
169.2 (C-2); MS, m/z (rel intensity) 409 (M111, 1), 407
(M121, 1), 264 (67), 157 (43), 155 (37), 91 (100), 69 (36),
65 (40), 57 (35), 55 (45). A solution of MCPBA (78%, 4 g,
18.1 mmol) in anhydrous CH2Cl2 (20 ml) was added to a
solution of 9a (5 g, 12.2 mmol) in anhydrous CH2Cl2
(30 ml) cooled at 08C. The mixture was allowed to rise to
258C, and stirring was continued for 3 h. Saturated aqueous
NaHCO3 was added, and the aqueous layer was extracted
with CH2Cl2. The extracts were dried and concentrated, and
the resulting solid was crystallized from Et2O to give pure
dihydropyridone 10a (2.4 g, 78%): IR (KBr) 1677, 1341,
General
Melting points were determined in a capillary tube on a
BuÈchi apparatus and are uncorrected. H and 13C NMR
1
spectra were recorded in CDCl3 solution on a Varian
Gemini 200 (200 and 50.3 MHz, respectively), a Varian
Gemini 300 (300 and 75 MHz, respectively), or a VX
R-500 (500 MHz) instrument. Chemical shifts are expressed
in parts per million (d) relative to internal Me4Si. IR spectra
were recorded on a Nicolet 205 FT-IR spectrophotometer.
Mass spectra were determined on a Hewlett±Packard
5988A mass spectrometer or on a Autospec-VG (HRMS).
Column and ¯ash chromatography were carried out on SiO2
(silica gel 60 SDS, 70±200 mm and 35±70 mm, respec-
tively) or Al2O3 (aluminiumoxid 90 Merck, activity II±III,
70±230 mesh ASTM). Drying of organic extracts during the
work-up of reactions was performed over anhydrous
Na2SO4. Microanalyses were performed on a Carlo Erba
Â
1106 analyzer by the Centro de Investigacion y Desarrollo
(CSIC), Barcelona.
1-(p-Toluenesulfonyl)-5,6-dihydro-2(1H)-pyridone (10a).
A solution of LHMDS (1 M in THF, 15 ml, 15 mmol) was
diluted in anhydrous THF (40 ml) under N2 at 2208C, and a
solution of d-valerolactam (1 g, 10 mmol) in THF (10 ml)
was slowly added. After 10 min, TsCl (1.9 g, 10 mmol) was
added, and the mixture was stirred at 2208C for 2 h. Finally,
H2O (20 ml) was added, and the aqueous layer was
extracted with Et2O. The combined organic extracts were
washed with brine, dried, and concentrated to give, after
chromatography (¯ash, SiO2, 1:1 hexane±AcOEt), 1-(p-
toluenesulfonyl)-2-piperidone (8a) (1.28 g, 50%): mp
141±1438C (Et2O) (Lit.9 144±1458C); IR (KBr) 1686,
1
1170 cm21; H NMR (200 MHz) 2.37 (s, 3H, Me), 2.48
(m, 2H, 5-H), 4.00 (t, Jˆ6.3 Hz, 2H, 6-H), 5.78 (dt, Jˆ9.9
and 1.8 Hz, 1H, 3-H), 6.75 (dt, Jˆ9.9, 4.2 Hz, 1H, 4-H),
7.26 (d, Jˆ8.4 Hz, 2H, Ts-m-H), 7.87 (d, Jˆ8.4 Hz, 2H,
Ts-o-H); 13C NMR (50.3 MHz) 21.5 (Me), 25.2 (C-5),
44.0 (C-6), 125.0 (C-4), 128.4 (C-o-Ts), 129.3 (C-m-Ts),
135.8 (C-p-Ts), 144.5 (C-3), 144.7 (C-i-Ts), 162.9 (C-2);
MS, m/z (rel intensity) 252 (M111, 1), 187 (59), 119
(100), 91 (63), 68 (32), 65 (41).
1350, 1173 cm21; H NMR (200 MHz) 1.80 (m, 2H, 5-H),
1
1.89 (m, 2H, 4-H), 2.42 (t, Jˆ6.6 Hz, 2H, 3-H), 2.43 (s, 3H,
Me), 3.92 (t, Jˆ6.2 Hz, 2H, 6-H), 7.31 (d, 2H, Ts-m-H),
7.61 (d, 2H, Ts-o-H); 13C NMR (50.3 MHz) 20.2 (C-4),
21.5 (Me), 23.1 (C-5), 33.9 (C-3), 46.8 (C-6), 128.6
(C-o-Ph), 129.6 (C-m-Ph), 135.9 (C-p-Ph), 144.6 (C-i-Ph),
170.2 (C-2); MS, m/z (rel intensity) 254 (M111, 1), 189
(47), 133 (89), 120 (38), 108 (23), 91 (100), 65 (80), 56 (27),
1-(Methoxycarbonyl)-5,6-dihydro-2(1H)-pyridone (10b).
A dispersion of NaH (60% in mineral oil, 4.5 g, 108 mmol)
under N2 was washed with anhydrous hexane and suspended

4032
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
in anhydrous CH2Cl2 (100 ml). d-Valerolactam (10.3 g,
100 mmol) was slowly added at 08C, and the mixture was
stirred for 15 min. Then, methyl chloroformate (15.5 ml,
200 mmol) was slowly added, and stirring was continued
at 258C for 3 h. After addition of H2O, the mixture was
extracted with CH2Cl2, and the combined organic extracts
were washed with brine, dried, and concentrated to give,
after chromatography (¯ash, SiO2, 1:1 hexane±AcOEt),
1-(methoxycarbonyl)-2-piperidone (8b)3a (12.4 g, 79%):
(C-p-Ts), 138.3 (C-o-PhSe), 144.8 (C-i-Ts), 166.7 and
168.8 (C-2 and CO2Bn); MS, m/z (rel intensity) 543
(M111, 0.1), 91 (100), 78 (26), 65 (23). A solution of
MCPBA (77%, 2.31 g, 12.5 mmol) in anhydrous CH2Cl2
(80 ml) was slowly added under N2 to a solution of piperi-
done 11a (3.2 g, 5.89 mmol) in anhydrous CH2Cl2 (50 ml)
cooled at 08C. The mixture was allowed to rise to 258C and
stirred for 3 h, poured into saturated aqueous NaHCO3, and
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried and concentrated to give dihydro-
pyridone 12a (2.1 g, 93%), which was used in the next
reaction without further puri®cation. An analytical sample
was obtained by crystallization: mp 94±958C (Et2O); IR
1
IR (NaCl) 1785, 1716 cm21; H NMR (200 MHz) 1.85
(m, 4H, 4-H and 5-H), 2.54 (m, 2H, 3-H), 3.74 (m, 2H,
6-H), 3.86 (s, 3H, OMe); 13C NMR (50.3 MHz) 20.1
(C-4), 22.3 (C-5), 34.5 (C-3), 46.3 (C-6), 53.5 (OMe),
154.6 (CO2Me), 171.0 (C-2). Operating as in the preparation
of 9a, from LDA (1.5 M in cyclohexane, 31.8 ml,
1.5 equiv.) in anhydrous THF (40 ml), piperidone 8b (5 g,
31.8 mmol) in anhydrous THF (40 ml), and PhSeCl (6.1 g,
31.8 mmol) in anhydrous THF (40 ml), 1-(methoxycar-
bonyl)-3-(phenylselanyl)-2-piperidone (9b) (3.7 g, 38%)
was obtained after ¯ash chromatography (SiO2, 1:1 hex-
(NaCl) 1741, 1692, 1355, 1168 cm21
;
1H NMR
(200 MHz) 2.40 (s, 3H, Me), 2.61 (td, Jˆ6.4, 4.5 Hz, 2H,
5-H), 4.06 (t, Jˆ6.4 Hz, 2H, 6-H), 5.18 (s, 2H, CH2Ph),
7.24±7.36 (m, 7H, PhH and Ts-m-H), 7.56 (t, Jˆ4.4 Hz,
1H, 4-H), 7.93 (d, Jˆ8.4 Hz, 2H, Ts-o-H); 13C NMR
(50.3 MHz) 21.2 (Me), 25.1 (C-5), 43.0 (C-6), 66.6
(CH2Ph), 127.9, 128.0, 128.2 and 129.1 (C-Ph), 135.0
(C-i-Bn), 135.3 (Ts-p-C), 144.6 (Ts-i-C), 151.4 (4-C),
159.1 and 162.2 (2-C and CO2Bn); MS, m/z (rel intensity)
386 (M111, 0.3), 97 (36), 83 (65), 71 (50), 69 (71), 57
(100), 55 (89). Anal. Calcd for C20H19O5NS: C, 62.32; H,
4.97; N, 3.63; S, 8.39. Found: C, 62.48; H, 4.96; N, 3.60; S,
8.19.
;
ane±AcOEt): IR (NaCl) 1724, 1667 cm21 1H NMR
(200 MHz) 1.52±1.88 (m, 4H, 4-H and 5-H), 3.60±3.90
(m, 2H, 6-H), 3.58 (t, Jˆ7.8 Hz, 1H, 3-H), 3.67 (s, 3H,
OMe), 7.26±7.34 (m, 3H, PhH), 7.62 (m, 2H, PhH); 13C
NMR (50.3 MHz) 20.8 (C-5), 28.5 (C-4), 44.7 (C-3), 46.3
(C-6), 53.8 (OMe), 128.3 (C-i-PhSe), 128.5 (C-p-PhSe),
129.1 (C-m-PhSe), 135.3 (C-o-PhSe), 155.0 (CO2Me),
170.5 (C-2). Operating as in the preparation of 10a, from
MCPBA (77%, 10 g, 58.13 mmol) in anhydrous CH2Cl2
(60 ml), and piperidone 9b (10.7 g, 34.18 mmol) in
anhydrous CH2Cl2 (60 ml) for 18 h, dihydropyridone 10b
(3.42 g, 65%) was obtained after ¯ash chromatography
3-(Benzyloxycarbonyl)-1-(methoxycarbonyl)-5,6-dihydro-
2(1H)-pyridone (12b). Operating as in the preparation of
11a, from LHMDS (1 M in THF, 30 ml, 30 mmol), piperi-
done 8b (2 g, 12.8 mmol) in anhydrous THF (60 ml), benzyl
chloroformate (1.8 ml, 12.8 mmol), and PhSeBr, generated
from Ph2Se2 (2.96 g, 9.48 mmol) and Br2 (0.456 ml,
8.87 mmol) in anhydrous THF, 3-(benzyloxycarbonyl)-1-
(methoxycarbonyl)-3-(phenylselanyl)-2-piperidone (11b)
(3.8 g, 68%) was obtained after ¯ash chromatography (SiO2,
1:1 hexane±AcOEt): IR (NaCl) 1776, 1725 cm21; 1H NMR
(300 MHz) 1.65 (m, 1H, 5-Heq), 1.83 (m, 1H, 5-Hax), 2.00
(ddd, Jˆ13.8, 10, 5.8 Hz, 1H, 4-Hax), 2.25 (dddd, Jˆ13.8,
7.9, 5.3, 0.9 Hz, 1H, 4-Heq), 3.45 (dddd, Jˆ13.3, 6.5, 5.9,
0.9 Hz, 1H, 6-Heq), 3.70 (ddd, Jˆ13.3, 8.1 5.5 Hz, 1H,
6-Hax), 3.86 (s, 3H, OMe), 5.15 and 5.24 (2d, Jˆ12.3 Hz,
1H each, CH2Ph), 7.25 (m, 3H, PhH), 7.35 (m, 5H, PhH),
7.49 (d, Jˆ8 Hz,2H, PhH); 13C NMR (50.3 MHz) 20.6
(C-5), 31.4 (C-4), 45.5 (C-6), 54.1 (OMe), 57.0 (C-3),
67.7 (CH2Ph), 128.2, 128.4, 128.7 and 129.7 (C-Ph),
135.0 (C-i-Bn), 138.4 (C-i-PhSe), 154.7 (CO2Me), 167.8
and 169.0 (C-2 and CO2Bn); MS, m/z (rel intensity) 447
(M11), 284 (22), 91 (100); 77 (17); 65 (17). Anal. Calcd
for C21H21NO5Se: C, 56.51; H, 4.74; N, 3.14. Found: C,
56.46; H, 4.81; N, 3.12. Piperidone 11b was oxidized by
two different methods. Method A: Ozone was bubbled
through a stirred solution of 11b (2.45 g, 5.49 mmol) in
anhydrous CH2Cl2 (50 ml) at 2788C until the solution
turned to a characteristic pale blue color. Then, the solution
was purged with N2 and stirred at 258C for 30 min. The
solvent was removed, and the residue was chromatographed
(¯ash, SiO2, 3:2 hexane±AcOEt) to yield dihydropyridone
(SiO2, 1:1 hexane±AcOEt): IR (NaCl) 1780, 1716 cm21
;
1H NMR (200 MHz) 2.44 (m, 2H, 5-H), 3.89 (s, 3H,
OMe), 3.96 (t, Jˆ6.6 Hz, 2H, 6-H), 5.99 (dt, Jˆ9 and
2 Hz, 1H, 3-H), 6.84 (dt, Jˆ9 and 4 Hz, 1H, 4-H); 13C
NMR (50.3 MHz) 24.4 (C-5), 43.6 (C-6), 53.6 (OMe),
125.5 (C-3), 144.2 (C-4), 154.5 (CO2Me), 163.2 (C-2).
3-(Benzyloxycarbonyl)-1-(p-toluenesulfonyl)-5,6-dihydro-
2(1H)-pyridone (12a). LHMDS (1 M in THF, 14 ml,
14 mmol) was slowly added to a solution of piperidone 8a
(1.61 g, 6.36 mmol) in anhydrous THF (90 ml) cooled at
2788C, and the mixture was stirred for 1 h. Then, benzyl
chloroformate (0.9 ml, 6.36 mmol) was added, stirring was
continued for 20 min, and PhSeBr, generated from Ph2Se2
(1.49 g, 4.77 mmol) and Br2 (0.228 ml, 4.44 mmol) in
anhydrous THF, was added. The mixture was stirred at
2788C for 30 min, allowed to rise to 258C, poured into
0.1 N aqueous HCl, and extracted with AcOEt. The
combined organic extracts were washed with saturated
aqueous NaHCO3, dried, and concentrated to give, after
chromatography (¯ash, SiO2, 3:1 hexane±AcOEt),
3-(benzyloxycarbonyl)-3-(phenylselanyl)-1-(p-toluenesul-
fonyl)-2-piperidone (11a) (2.3 g, 67%): IR (NaCl) 1731,
1
1699, 1355, 1170 cm21; H NMR (200 MHz) 1.64±1.75
(m, 1H, 4-Hax), 1.83±2.00 (m, 2H, 5-H), 2.20 (dt, Jˆ14,
5.3 Hz, 1H, 4-Heq), 2.41 (s, 3H, Me), 3.70±3.79 (m, 2H,
6-H), 5.08 (s, 2H, CH2Ph), 7.20±7.45 (m, 12H, PhH), 7.90
(d, Jˆ8.4 Hz, 2H, Ts-o-H); 13C NMR (50.3 MHz): 21.2
(C-5), 21.6 (Me), 31.3 (C-4), 45.7 (C-6), 55.5 (C-3), 67.7
(CH2Ph), 125.8 (C-i-PhSe), 128.0, 128.2, 128.4, 128.7,
128.8, 129.3 and 129.8 (C-Ph), 134.9 (C-i-Bn), 135.3
1
12b (1.4 g, 87%): IR (KBr) 1773, 1717, 1704 cm21; H
NMR (300 MHz) 2.54 (q, 2H, 5-H), 3.89 (s, 3H,OMe),
3.96 (t, Jˆ6.5 Hz, 2H, 6-H), 5.27 (s, 2H, CH2Ph), 7.37
(m, 5H, Ph-H), 7.57 (t, Jˆ4.4 Hz, 1H, 4-H); 13C NMR
(75 MHz) 24.6 (C-5), 43.3 (C-6), 54.1 (OMe), 67.1

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4033
(CH2Ph), 128.2 and 128.5 (C-Ph), 135.3 and 135.4 (C-3 and
C-i-Ph), 149.9 (C-4), 154.6 (CO2Me), 159.6 and 163.5 (C-2
and CO2Bn); MS, m/z (rel intensity) 183 (23), 157 (21), 155
(50), 112 (17), 91 (100), 65 (28). Anal. Calcd for
C15H15NO5: C, 62.28; H, 5.23; N, 4.84. Found: C, 62.12;
H, 5.29; N, 4.77. Method B: Operating as in the preparation
of 12a, a solution of MCPBA (80%, 1.6 g, 7.6 mmol) and
piperidone 11b (3.4 g, 7.6 mmol) in anhydrous CH2Cl2
(60 ml) was allowed to react for 1 h 30 min. After workup
and crystallization from hexane±AcOEt, dihydropyridone
12b (1.64 g, 74%), was obtained. When an excess of
MCPBA was used, 3-(benzyloxycarbonyl)-3,4-epoxy-1-
(methoxycarbonyl)-2-piperidone was isolated as the
1.4 Hz, 1H, 6-Heq), 4.26 (m, 1H, 5-H), 7.28 (d, Jˆ8.8 Hz,
2H, Ts-m-H), 7.89 (d, Jˆ8.4 Hz, 2H, Ts-o-H); 13C NMR
(75 MHz) 24.9 (Me2Si), 17.8 (C±Si), 21.5 (MeTs), 25.5
(t-Bu), 28.1 and 29.4 (C-3 and C-4), 53.3 (C-6), 63.9
(C-5), 128.4 (C-o-Ts) 129.1 (C-m-Ts), 136.0 (C-p-Ts),
144.5 (C-i-Ts), 169.6 (C-2); MS, m/z (rel intensity) 326
(100), 262 (27), 229 (30), 155 (84), 91 (64), 73 (61). Anal.
Calcd for C18H29NO4SiS: C, 56.37; H, 7.63; N, 3.65; S, 8.35.
Found: C, 56.60; H, 7.74; N, 3.60; S, 8.13.
(S)-(1)-3-(Benzyloxycarbonyl)-5-(tert-butyldimethylsilyl-
oxy)-1-(p-toluenesulfonyl)-5,6-dihydro-2(1H)-pyridone
(16a). Operating as in the preparation of 11a, from LHMDS
(1 M in THF, 12 ml, 12 mmol), piperidone 14a (2.0 g,
5.21 mmol) in anhydrous THF (100 ml), benzyl chloro-
formate (0.77 ml, 5.73 mmol), and PhSeBr (1.59 g, 6.77
mmol) in anhydrous THF (25 ml), two epimeric (S)-3-
(benzyloxycarbonyl)-5-(tert-butyldimethylsilyloxy)-3-
(phenylselanyl)-1-(p-toluenesulfonyl)-2-piperidones (15a)
(7:3, 2.97 g, 85%) were obtained after ¯ash chromatography
(SiO2, 4:1 hexane±AcOEt). Major epimer (oil): [a]2D0ˆ
241.7 (c 0.7, CHCl3); IR (NaCl) 1730, 1708, 1361,
1
major compound: IR (KBr) 1780, 1751, 1731 cm21; H
NMR (300 MHz) 2.22 (ddd, Jˆ15.2, 12.7, 5.7 Hz, 1H,
5-Hax), 2.41 (dm, Jˆ15.3 Hz, 1H, 5-Heq), 3.48 (td, Jˆ13,
4 Hz, 1H, 6-Hax), 3.80 (d, Jˆ2.7 Hz, 1H, 4-H), 4.08 (s, 3H,
Me), 4.12 (dd, Jˆ13.2, 5.6 Hz, 1H, 6-Heq), 5.3 and 5.8 (2d,
Jˆ12.2 Hz, 1H each, CH2Ph), 7.38 (m, 5H, PhH); 13C NMR
(75 MHz) 23.3 (C-5), 38.9 (C-6), 54.3 (OMe), 57.9 (C-4),
58.2 (C-3), 67.8 (CH2Ph), 128.3, 128.4 and 128.5 (C-Ph),
134.6 (C-i-Ph), 153.8 (CO2Me), 163.7 and 164.5 (C-2 and
CO2Bn); MS, m/z (rel intensity) 171 (39), 112 (34), 91
(100), 65 (18). Anal. Calcd for C16H14NO6: C, 59.01; H,
4.95; N, 4.59. Found: C, 58.98; H, 5.08; N, 4.56.
1
1172 cm21; H NMR (300 MHz) 20.06 and 0.01 (2s, 3H
each, Me2Si), 0.83 (s, 9H, t-Bu), 1.85 (dd, Jˆ14.6, 6.6 Hz,
1H, 4-H), 2.44 (s, 3H, MeTs), 2.49 (dd, Jˆ14, 6.6 Hz, 1H, 4-
H), 3.39 (dd, Jˆ13.5, 3.8 Hz, 1H, 6-H), 3.80 (dd, Jˆ13.5,
4.7 Hz, 1H, 6-H), 3.95 (m, 1H, 5-Hax), 5.06 and 5.15 (2d,
Jˆ12.1 Hz, 1H each, CH2Ph), 7.2±7.4 (m, 12H, PhH), 7.95
(d, Jˆ8.25 Hz, 2H, Ts-o-H); 13C NMR (75 MHz) 25.0 and
24.9 (Me2Si), 17.9 (C±Si), 21.7 (MeTs), 25.6 (t-Bu), 40.7
(C-4), 51.3 (C-6), 54.0 (C-3), 64.5 (C-5), 67.9 (CH2Ph),
125.6 (C-i-Ph), 128.3, 128.5, 128.8, 129.1, 129.3 and
129.9 (C-Ph), 134.7 (C-p-Ts), 135.3 (C-i-SePh), 138.3
(C-o-SePh), 144.8 (C-i-Ts), 166.2 (CO2Bn), 168.2 (C-2);
MS, m/z (rel intensity) 352 (6), 229 (7), 155 (8), 91 (100),
79 (8), 78 (12), 77 (12). Anal. Calcd for C32H39NO6SSeSi:
C, 57.13; H, 5.84; N, 2.08; S, 4.77. Found: C, 57.08; H, 5.95;
N, 2.03; S, 4.68. Minor epimer (solid): mp 104±1068C
(Et2O); [a]2D0ˆ147.2 (c 0.5, CHCl3); IR (KBr) 1737,
(S)-(2)-5-(tert-Butyldimethylsilyloxy)-1-(p-toluenesulfo-
nyl)-2-piperidone (14a). A mixture of (S)-(2)-5-hydroxy-
2-piperidone (13)4 (2 g, 17.3 mmol), tert-butyldimethylsilyl
chloride (3.14 g, 20.8 mmol), and imidazole (2.94 g,
43.4 mmol) in DMF (14 ml) was stirred under N2 at 258C
for 1 h. The solvent was evaporated, and AcOEt (100 ml)
and 5% aqueous citric acid (50 ml) were added. The mixture
was extracted with AcOEt, and the organic extracts were
washed with 5% aqueous citric acid and saturated aqueous
NaHCO3. The combined organic extracts were dried and
concentrated, and the resulting oil was chromatographed
(Al2O3, CH2Cl2) to give (S)-(2)-5-(tert-butyldimethylsilyl-
oxy)-2-piperidone (3.64 g, 91%): [a]2D0ˆ212.09 (c 2,
MeOH); IR (KBr) 3145, 3043, 1644 cm21
;
1H NMR
1665, 1359, 1176 cm21; H NMR (300 MHz) 20.02 and
1
(300 MHz) 0.07 and 0.08 (2s, 3H each, Me2Si), 0.88 (s,
9H, t-Bu), 1.87 (q, Jˆ6 Hz, 2H, 4-H), 2.31 (dt, Jˆ17.6,
6.1 Hz, 1H, 3-H), 2.58 (dt, Jˆ17.6, 7.5 Hz, 1H, 3-H), 3.18
(ddd, Jˆ12.5, 5, 2.5 Hz, 1H, 6-Hax), 3.39 (ddd, Jˆ12.5, 3.9,
2.1 Hz, 1H, 6-Heq), 4.08 (qn, Jˆ4.5 Hz, 1H, 5-Hax), 6.45
(br s, 1H, NH); 13C NMR (75 MHz) 24.9 and 24.8 (Me2Si),
17.9 (C±Si), 25.6 (t-Bu), 27.4 and 28.8 (C-3 and C-4), 49.2
(C-6), 64.0 (C-5), 172.1 (C-2). n-BuLi (1.6 M in hexane,
8.9 ml, 14.2 mmol) was added to a solution of the above
protected piperidone (3 g, 13.1 mmol) in anhydrous THF
(120 ml) cooled at 08C, and the solution was stirred at 08C
for 25 min. Then, TsCl (3.75 g, 19.6 mmol) and DMAP
(0.37 g, 3 mmol) were added, and the mixture was allowed
to rise to 258C, stirred for 3 h, poured into saturated aqueous
NaHCO3, and extracted with AcOEt. Concentration of the
dried organic extracts followed by ¯ash chromatography
(SiO2, CH2Cl2) gave 14a (5.68 g, 57%) as a yellow solid:
mp 137±1388C (Et2O); [a]2D0ˆ210.3 (c 1, CHCl3); IR
0.02 (2s, 3H each, Me2Si), 0.81 (s, 9H, t-Bu), 2.17 (dd,
Jˆ14.3, 3.6 Hz, 1H, 4-Hax), 2.36 (s, 3H, MeTs), 2.50
(ddd, Jˆ14.3, 5.1, 1.3 Hz, 4-Heq), 3.78 (ddd, Jˆ12.7, 5,
1.3 Hz, 1H, 6-Heq), 3.86 (dd, Jˆ12.6, 3.6 Hz, 1H, 6-Hax),
4.19 (m, 1H, 5-Hax), 4.93 and 5.07 (2 d, Jˆ12.8 Hz, 1H
each, CH2Ph), 7.1±7.4 (m, 10 H, PhH), 7.53 (d, Jˆ8.3 Hz,
2H, Ts-m-H), 7.89 (d, Jˆ8.3 Hz, 2H, Ts-o-H); 13C NMR
(75 MHz) 25.2 and 25.0 (Me2Si), 18.0 (C±Si), 21.6
(MeTs), 25.6 (t-Bu), 39.7 (C-4), 52.4 (C-6), 63.8 (C-5),
67.4 (CH2Ph), 126.4 (C-i-Ph), 127.4, 127.8, 128.2, 128.6,
128.7, 129.1 and 129.8 (C-Ph), 134.9 (C-i-Ts), 135.2 (C-i-
SePh), 138.2 (C-o-SePh), 144.6 (C-p-Ts), 166.1 (CO2Bn),
168.9 (C-2); MS, m/z (rel intensity) 352 (6), 229 (6), 255 (8),
91 (100), 79 (5), 78 (9), 77 (9). Anal. Calcd for
C32H39NO6SSeSi: C, 57.13; H, 5.84; N, 2.08; S, 4.77.
Found: C, 56.77; H, 5.96; N, 2.03; S, 4.58. Operating as
in the preparation of 12a, a solution of selanides 15a
(118 mg, 0.17 mmol) and MCPBA (77%, 58 mg,
0.26 mmol) in anhydrous CH2Cl2 (7 ml) was stirred for
1.5 h to give pure dihydropyridone 16a (61 mg, 67%) as a
yellow solid after crystallization: mp 140±1438C (Et2O);
[a]2D0ˆ110.7 (c 1, CHCl3); IR (KBr) 1714, 1679, 1352,
1
(KBr) 1686, 1355, 1167 cm21; H NMR (300 MHz) 0.08
and 0.11 (2s, 3H each, Me2Si), 0.85 (s, 9H, t-Bu), 1.85
(m, 2H, 4-H), 2.38 (ddd, Jˆ17, 6.2, 4.4 Hz, 1H, 3-Heq),
2.41 (s, 3H, MeTs), 2.6 (ddd, Jˆ17, 10, 7 Hz, 1H, 3-Hax),
3.83 (dd, Jˆ12.4, 3 Hz, 1H, 6-Hax), 3.97 (ddd, Jˆ12.4, 4,
1
1166 cm21; H NMR (300 MHz) 0.13 and 0.16 (2s, 3H

4034
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
each, Me2Si), 0.90 (s, 9H, t-Bu), 2.42 (s, 3H, MeTs), 3.88
(dd, Jˆ12.9, 7.9 Hz, 1H, 6-Hax), 4.21 (ddd, Jˆ12.7, 4.8,
0.9 Hz, 1H, 6-Heq), 4.63 (ddd, Jˆ7.8, 4.8, 3 Hz, 1H,
5-Hax), 5.21 (s, 2H, CH2Ph), 7.31 (m, 3H, 4-H and Ts-m-
H), 7.93 (d, Jˆ8Hz, 2H, Ts-o-H); 13C NMR (75 MHz) 24.7
(Me2Si), 17.9 (C±Si), 21.6 (MeTs), 25.5 (t-Bu-C±Si), 49.9
(C-6), 63.9 (C-5), 67.3 (CH2Ph), 127.8, 128.2, 128.3 and
128.4 (C-Ph), 128.6 (C-m-Ts), 129.4 (C-o-Ts), 135.1
(C-3), 135.4 (C-p-Ts), 144.9 (C-i-Ts), 151.7 (C-4), 158.5
(CO2Bn), 162.4 (C-2); MS, m/z (rel intensity) 275 (6), 155
(6), 108 (6), 92 (12), 91 (100). Anal. Calcd for
C26H33NO6SSi: C, 60.56; H, 6.45; N, 2.72; S, 6.22.
Found: C, 60.37; H, 6.57; N, 2.62; S, 6.01.
until disappearance of the dienophile by TLC. After
evaporation of the solvent, the residue was chromato-
graphed (¯ash, SiO2) unless otherwise indicated.
Method B: An excess of the diene was added to a solution of
the 5,6-dihydro-2(1H)-pyridone in anhydrous C6H6, and the
mixture was stirred at re¯ux temperature until disappear-
ance of the dienophile by TLC. After evaporation of the
solvent, the residue was extracted with AcOEt or CH2Cl2.
The organic extracts were dried and concentrated, and the
crude product was chromatographed (¯ash, SiO2) unless
otherwise indicated.
Method C: A solution of the 5,6-dihydro-2(1H)-pyridone in
anhydrous CH2Cl2 was slowly added to a suspension of
anhydrous ZnBr2 (1 equiv.) in anhydrous CH2Cl2 at 08C.
Then, an excess of the diene was added dropwise, and the
mixture was stirred either at 08C or at 258C, depending on
the reactivity of the dienophile, until disappearance of the
dienophile by TLC. A saturated aqueous NaHCO3 solution
was added, and the mixture was extracted with CH2Cl2. The
combined organic extracts were dried and concentrated, and
the residue was chromatographed (¯ash, SiO2) unless other-
wise indicated.
(S)-(1)-3-(Benzyloxycarbonyl)-5-(tert- butyldimethylsilyl-
oxy)-1-(methoxycarbonyl)-5,6-dihydro-2(1H)-pyridone
(16b). Operating as in the preparation of 11a, from LHMDS
(1 M in THF, 3.8 ml, 3.8 mmol), piperidone 14b10 (0.5 g,
1.74 mmol) in anhydrous THF (10 ml), benzyl chloro-
formate (0.23 ml, 1.74 mmol), and PhSeBr (0.57 g, 2.41
mmol) in anhydrous THF (6 ml), an epimeric mixture of
(S)-3-(benzyloxycarbonyl)-5-(tert-butyldimethylsilyloxy)-
1-(methoxycarbonyl)-3-(phenylselanyl)-2-piperidones (15b)
(2.5:1, 0.67 g, 67%) was obtained after ¯ash chroma-
tography (SiO2, CH2Cl2). The major epimer could be sepa-
1
rated: IR (NaCl) 1780, 1730 cm21; H NMR (200 MHz)
Diels±Alder reactions from Danishefsky's diene 1
0.02 (s, 6H, Me2Si), 0.87 (s, 9H, t-Bu), 2.06 (dd, Jˆ14,
6.6 Hz, 1H, 4-H), 2.50 (dd, Jˆ14, 6.2 Hz, 1H, 4-H), 3.31
(dd, Jˆ13.6, 4.8 Hz, 1H, 6-H), 3.82 (dd, Jˆ13.7, 5.3 Hz,
1H, 6-H), 3.94 (s, 3H, CO2Me), 3.96 (m, 1H, 5-H), 5.1 and
5.2 (2d, Jˆ12.2 Hz, 1H each, CH2Ph), 7.41 (m, 10H, PhH);
13C NMR (50.3 MHz) 25.1 and 24.9 (Me2Si), 17.8 (C±Si),
25.5 (t-Bu), 40.9 (C-4), 51.1 (C-6), 54.3 (CO2Me), 55.1
(C-3), 64.0 (C-5), 67.9 (CH2Ph), 128.4, 128.5, 128.8 and
129.8 (C-Ph), 134.8 (C-i-Bn), 138.4 (C-o-SePh), 154.4
(CO2Me), 167.2 (CO2Bn), 168.7 (C-2); MS, m/z (rel inten-
sity) 577 (M111, 0.002), 520 (2), 272 (12), 91(100), 77 (5),
59 (6). Anal. Calcd for C27H35NO6SeSi´1/4H2O: C, 55.8; H,
6.16; N, 2.41. Found: C, 55.55; H, 6.11; N, 2.63. Selanides
15b (676 mg, 1.17 mmol) in anhydrous CH2Cl2 (5 ml) were
treated with O3 as in the preparation of 12b (Method A). The
crude mixture was poured into brine and extracted with
CH2Cl2. The combined organic extracts were dried and
concentrated, and the residue was chromatographed (¯ash,
SiO2, 7:3 hexane±AcOEt) to give dihydropyridone 16b
(386 mg, 78%): [a]D20ˆ110.5 (c 1, CHCl3); IR (KBr)
With dihydropyridone 10a. Method A: From 10a (500 mg,
1.98 mmol) and diene 1 (1.34 ml, 6.94 mmol) in p-cymene
(15 ml) for 6 h, a residue was obtained. Anhydrous THF
(50 ml) and CSA (300 mg, 1.29 mmol) were added to the
residue, and the resulting solution was stirred at 08C for 1 h.
After addition of saturated aqueous NaHCO3, the mixture
was extracted with AcOEt. Concentration of the dried
organic extracts afforded, after chromatography (Et2O),
1,6-dioxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,6,7-octahydro-
isoquinoline (17a) (217 mg, 34%): mp 156±1598C (Et2O);
1
IR (KBr) 1716, 1679, 1678, 1347, 1174 cm21; H NMR
(300 MHz) 1.65 (qd, Jˆ12.7, 4.2 Hz, 1H, 4-Hax), 2.09
(m, 1H, 4-Heq), 2.15 (dd, Jˆ14.6, 12.4 Hz, 1H, 5-Hax),
2.44 (s, 3H, Me), 2.54 (dd, Jˆ14.7, 4.5 Hz, 1H, 5-Heq),
2.67±2.82 (m, 1H, 4a-H), 3.00 (dd, Jˆ23.4, 3.1 Hz, 1H,
7-H), 3.07 (ddd, Jˆ23.1, 4.8, 2.5 Hz, 1H, 7-H), 3.58 (td,
Jˆ12.7, 2.9 Hz, 1H, 3-Hax), 4.39 (ddd, Jˆ12.7, 4.2, 3 Hz,
1H, 3-Heq), 7.08 (m, 1H, 8-H), 7.24 (d, Jˆ8.0 Hz, 2H,
Ts-m-H), 7.83 (d, Jˆ8.3 Hz, 2H, Ts-o-H). Anal. Calcd for
C16H17O4NS: C, 60.17; H, 5.37; N, 4.39; S, 10.04. Found: C,
59.65; H, 5.27; N, 4.18; S, 9.62.
1
1780, 1727, 1389 cm21; H NMR (200 MHz) 0.15 (s, 6H,
Me2Si), 0.92 (s, 9H, t-Bu), 3.67 (dd, Jˆ12.8, 9.2 Hz, 1H,
6-Hax), 3.90 (s, 3H, OMe), 4.12 (ddd, Jˆ12.8, 5.1, 1.5 Hz,
1H, 6-Heq), 4.63 (ddd, Jˆ9, 5.1, 2.8 Hz, 1H, 5-Hax), 5.30
(s, 2H, CH2Ph), 7.36 (m, 6H, 4-H, PhH); 13C NMR
(50.3 MHz) 25.0 (Me2Si), 17.7 (C±Si), 25.3 (t-Bu), 50.0
(C-6), 54.0 (OMe), 63.6 (C-5), 67.1 (CH2Ph), 127.9, 128.1
and 128.3, (C-Ph, C-3), 135.0 (C-i-Bn), 151.7 (C-4), 158.5
(CO2Bn), 162.2 (C-2); MS, m/z (rel intensity) 240 (14), 91
(100). Anal. Calcd for C21H29NO6Si´1/2H2O: C, 58.86; H,
7.06; N, 3.27. Found: C, 58.82; H, 7.08; N, 3.42.
With dihydropyridone 12a. Method A: Dihydropyridone
12a (500 mg, 1.29 mmol) was allowed to react with diene 1
(0.89 ml, 4.5 mmol) in p-cymene (10 ml) for 1 h. After
CSA treatment (300 mg, 08C, 1 h), as above, followed by
chromatography (65:35 hexane±AcOEt), adducts endo-18a
(250 mg, 40%) and its C-8 epimer exo-18a (115 mg, 18%)
were obtained. (4aRS,8SR,8aSR)-8a-(Benzyloxycarbo-
nyl)-8-methoxy-1,6-dioxo-2-(p-toluenesulfonyl)perhydro-
isoquinoline (endo-18a): mp 90±918C (Et2O); IR (KBr)
1744, 1724, 1679, 1359, 1174 cm21;1H NMR (200 MHz)
1.97 (m, 1H, 4-Hax) 2.22 (m,1H, 4-Heq), 2.28 (dd, Jˆ15,
6 Hz, 1H, 5-Hax), 2.41 (ddd, Jˆ15, 3, 1.2 Hz, 1H, 5-Heq),
2.41 (s, 3H, MeTs), 2.65 (ddd, Jˆ15.4, 3, 1.2 Hz, 1H,
7-Heq), 2.83 (m, 1H, 4a-H), 2.82 (s, 3H, OMe), 2.83 (dd,
General procedures for Diels±Alder cycloadditions
Method A: An excess of the diene was added to a solution of
the 5,6-dihydro-2(1H)-pyridone in distilled and degased
p-cymene, and the mixture was stirred at re¯ux temperature

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4035
Jˆ16, 3.6 Hz, 1H, 7-Hax), 3.90 (ddd, Jˆ12.6, 8.8, 4.5 Hz,
1H, 3-Hax), 4.09 (dt, Jˆ12.7, 5 Hz, 1H, 3-Heq), 4.29 (td,
Jˆ2.8, 1 Hz, 1H, 8-Heq), 5.20 and 5.05 (2d, Jˆ12.3 Hz, 1H
each, CH2Ph), 7.2±7.4 (m, 7H, PhH and Ts-m-H), 7.89 (d,
Jˆ8.3 Hz, 2H, Ts-o-H); MS, m/z (rel intensity) 286 (6), 256
(23), 91 (100), 65 (12). Anal. Calcd for C25H27O7NS: C,
61.84; H, 5.60; N, 2.88; S, 6.60. Found: C, 61.84; H, 5.76;
N, 2.70; S, 6.55. (4aRS,8RS,8aSR)-Isomer (exo-18a): mp
150±1518C (Et2O); IR (KBr) 1729, 1720, 1702, 1359,
anhydrous THF (6 ml) at 258C for 1 h, adducts 18b (100 mg,
15%) and 19b (130 mg, 21%) were obtained after chroma-
tography (4:1 hexane±AcOEt). (4aRS,8SR,8aSR)-8a-
(Benzyloxycarbonyl)-8-methoxy-2-(methoxycarbonyl)-
1,6-dioxoperhydroisoquinoline (endo-18b): IR (NaCl)
1
1775, 1725 cm21; H NMR (300 MHz) 1.92 (dq, Jˆ11,
4 Hz, 1H, 4-H), 2.15 (m, 1H, 4-H), 2.32 (dd, Jˆ15, 6 Hz,
1H, 5-Hax), 2.46 (ddd, Jˆ15, 6.3, 1.1 Hz, 1H, 5-Heq), 2.76
(ddd, Jˆ16, 3, 1.1 Hz, 1H, 7-Heq), 2.81 (m, 1H, 4a-H), 2.91
(dd, Jˆ16, 3.4 Hz, 1H, 7-Hax), 3.26 (s, 3H, OMe), 3.71
(ddd, Jˆ13, 9, 5 Hz, 1H, 3-Heq), 3.87 (m, 1H, 3-Hax),
3.89 (s, 3H, CO2Me), 4.51 (td, Jˆ3.2, 1 Hz, 1H, 8-H),
5.20 and 5.24 (2d, Jˆ12 Hz, 1H each, CH2Ph), 7.35 (m,
5H, PhH). Anal. Calcd for C20H23NO7: C, 61.69; H, 5.95;
N, 3.60. Found: C, 61.59; H, 6.03; N, 3.53. cis-8a-(Benzyl-
oxycarbonyl)-2-(methoxycarbonyl)-1,6-dioxo-1,2,3,4,4a,
5,6,8a-octahydroisoquinoline (19b): IR (NaCl) 1780,
1174 cm21
;
1H NMR (200 MHz) 1.64 (dtd, Jˆ14.5, 7,
3.2 Hz, 1H, 4-H), 1.97 (t, Jˆ14 Hz, 1H, 5-Hax), 2.34
(ddd, Jˆ14.6, 5.3, 2 Hz, 1H, 5-Heq), 2.41 (s, 3H, MeTs),
2.43 (dd, Jˆ15.5, 3 Hz, 1H, 7-Hax), 2.51 (m, 1H, 4-H), 2.58
(ddd, Jˆ15.5, 3, 2 Hz, 1H, 7-Heq), 3.00 (s, 3H, OMe), 3.23
(m, 1H, 4a-H), 3.55 (ddd, Jˆ13.6, 7.7, 6.2 Hz, 1H, 3-Hax),
4.14 (dt, Jˆ13.6, 6.2 Hz, 1H, 3-Heq), 4.38 (t, Jˆ3 Hz, 1H,
8-H), 5.24 and 4.96 (2d, Jˆ12 Hz, 1H each, CH2Ph), 7.20±
7.35 (m, 7H, PhH), 7.86 (d, Jˆ8.4 Hz, 2H, Ts-o-H); MS,
m/z (rel intensity) 350 (7); 91 (100); 65 (12); 57 (10); 55
(10). Anal. Calcd for C25H27O7NS: C, 61.84; H, 5.60; N,
2.88; S, 6.60. Found: C, 61.89; H, 5.69; N, 2.89; S, 6.60.
Method B: Dihydropyridone 12a (500 mg, 1.29 mmol) was
allowed to react with diene 1 (0.5 ml, 2.6 mmol) in C6H6
(10 ml) for 30 min. After CSA treatment (300 mg, 08C, 1 h)
as above, followed by chromatography (3:1 hexane±
AcOEt), adducts 18a (250 mg, 41%) and 19a (170 mg,
30%) were obtained. cis-8a-(Benzyloxycarbonyl)-1,6-
dioxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,6,8a-octahydro-
isoquinoline (19a): mp 159±1618C (Et2O); IR (KBr) 1739,
1
1720, 1690 cm21; H NMR (200 MHz) 1.91 (m, 2H, 4-H),
2.34 (dd, Jˆ16.5, 6 Hz, 1H, 5-H), 2.51 (dd, Jˆ16, 5 Hz,
5-H), 3.05 (m, 1H, 4a-H), 3.59 (ddd, Jˆ13, 10.7, 4.5 Hz,
1H, 3-H), 3.88 (s, 3H, OMe), 3.97 (dt, Jˆ13, 4.7 Hz, 1H,
3-H), 5.23 and 5.27 (2d, Jˆ12.2 Hz, 1H each, CH2Ph), 6.19
(d, Jˆ10 Hz, 1H, 7-H), 6.93 (dd, Jˆ10, 1.1 Hz, 1H, 8-H),
7.34 (m, 5H, PhH). Anal. Calcd for C19H19NO6: C, 63.86; H,
5.36; N, 3.92. Found: C, 63.60; H, 5.40; N, 3.78. Method B:
From 12b (510 mg, 1.76 mmol) and diene 1 (0.7 ml, 3.5
mmol) in C6H6 (10 ml) for 2 h, and then from CSA
(410 mg, 1.77 mmol) in anhydrous THF (10 ml) at 08C for
1 h, adducts 18b (122 mg, 17%) and 19b (390 mg, 62%)
were obtained after chromatography (4:1 hexane±AcOEt).
1
1687, 1676, 1354, 1167 cm21; H NMR (200 MHz) 1.85
(dtd, Jˆ14, 10 and 5 Hz, 1H, 4-Hax), 2.05 (dq, Jˆ14 and
4.5 Hz, 1H, 4-Heq), 2.29 (dd, Jˆ17 and 6 Hz, 1H, 5-H),
2.43 (s, 3H, Me), 2.47 (dd, Jˆ17 and 5 Hz, 1H, 5-H), 2.97
(m, 1H, 4a-H), 3.75 (ddd, Jˆ13, 9 and 4.5 Hz, 1H, 3-Heq),
4.19 (dt, Jˆ13 and 5 Hz, 1H, 3-Hax), 5.06 and 5.17 (2d,
Jˆ12 Hz, 1H each, CH2Ph), 6.14 and 6.77 (2d, Jˆ10 Hz,
1H each, 7-H and 8-H), 7.3 (m, 8H, PhH and Ts-m-H), 7.88
(d, Jˆ8.4 Hz, 2H, Ts-o-H); Anal. Calcd for C24H23O6NS: C,
63.56; H, 5.11; N, 3.09; S, 7.07. Found: C, 63.57; H, 5.21;
N, 3.28; S, 6.98. cis-8a-(Benzyloxycarbonyl)-8-methoxy-
1-oxo-2-(p-toluenesulfonyl)-6-(trimethylsilyloxy)-1,2,3,4,
4a,5,6,8a-octahydroisoquinoline was also isolated (55 mg,
With dihydropyridone 16a. Method A: From 16a (516 mg,
1 mmol) and diene 1 (0.67 ml, 3.5 mmol) in p-cymene
(15 ml) for 1.5 h, adducts 20a (14%, one diastereomer of
unknown con®guration at C-8) and 22a (18%) were
obtained after chromatography (CH2Cl2±1% MeOH). An
analytical sample of (4S,4aR,8aS)-8a-(benzyloxycarbo-
nyl)-4-(tert-butyldimethylsilyloxy)-8-methoxy-1,6-dioxo-
2-(p-toluenesulfonyl)perhydroisoquinoline (20a) was
obtained by chromatography (CH2Cl2±1% MeOH): IR
(KBr) 1743, 1725, 1694, 1357, 1172 cm21 1H NMR
;
(300 MHz) 0.13 (s, 6H, Me2Si), 0.91 (s, 9H, t-Bu), 2.05
(dd, Jˆ15, 7 Hz, 1H, 5-H), 2.40 (s, 3H, MeTs), 2.65 (m,
2H, 5-H, 7-H), 2.84 (m, 2H, 4-Ha and 7-H), 2.94 (s, 3H,
OMe), 3.39 (dd, Jˆ13.6, 11 Hz, 1H, 3-Hax), 4.30 (m, 3H,
3-Heq, 4-H and 8-H), 5.06 and 5.14 (2d, Jˆ12.5 Hz, 1H
each, CH2Ph), 7.15±7.39 (m, 7H, PhH), 7.87 (d, Jˆ
8.2 Hz, 2H, Ts-o-H). (4S,4aS,8aS)-8a-(Benzyloxycarbo-
nyl)-4-(tert-butyldimethylsilyloxy)-1,6-dioxo-2-(p-toluene-
sulfonyl)-1,2,3,4,4a,5,6,8a-octahydroisoquinoline (22a):
mp 133±1358C (Et2O); [a]2D0ˆ246.8 (c 0.25, CHCl3); IR
1
8%): IR (KBr) 1735, 1687, 1366, 1177 cm21; H NMR
(300 MHz) 0.13 (m, 9H, Me3Si), 1.65±1.69 (dm,
Jˆ12.5 Hz, 1H, 4-H), 1.84 (d, Jˆ15.6 Hz, 1H, 5-Hax),
1.98 (dd, 15.6, 4.7 Hz, 1H, 5-Heq), 2.40 (s, 3H, Me-Ts),
2.51±2.66 (m, 1H, 4a-H), 2.67±2.75 (m, 1H, 4-H), 2.82
(s, 3H, OMe), 3.86 (td, Jˆ12.1, 5.5 Hz, 1H, 3-Hax), 4.13
(m, 1H, 3-Heq), 4.31 (d, Jˆ5.2 Hz, 1H, 8-H), 4.99 (d,
Jˆ12.4 Hz, 1H, CH2Ph), 5.08±5.16 (m, 1H, 7-H), 5.22 (d,
Jˆ12 Hz, 1H, CH2Ph), 7.26±7.31 (m, 7H, PhH), 7.89 (d,
Jˆ7.8 Hz, 2H, Ts-o-C); 13C NMR (50.3 MHz): 0.2 (Me3Si),
21.6 (MeTs), 24.6 (C-4), 32.7 (C-4a), 33.1 (C-5), 46.3 (C-3),
57.6 (OMe), 59.2 (C-8a), 67.4 (CH2Ph), 76.0 (C-8), 100.9
(C-7), 128.0, 128.1, 128.3, 128.5, and 129.0 (C-Ph), 135.7
(C-p-Ts), 136.1 (C-i-Bn), 144.4 (C-i-Ts), 150.2 (C-6), 167.5
and 168.8 (C-1 and CO2Bn). Anal. Calcd for C29H35O7NSSi:
C, 61.14; H, 6.19; N, 2.46; S, 5.63. Found: C, 60.53; H, 6.46;
N, 2.55; S, 5.19.
(KBr) 1748, 1698, 1686, 1359, 1176 cm21 1H NMR
;
(300 MHz) 20.02 and 0.05 (2s, 3H each, Me2Si), 0.75 (s,
9H, t-Bu), 2.23 (dd, Jˆ17, 6 Hz, 1H, 5-H), 2.41 (s, 3H,
MeTs), 2.62 (dd, Jˆ17, 6.4 Hz, 1H, 5-H), 2.95 (td, Jˆ6,
3 Hz, 1H, 4a-H), 3.84 (dd, Jˆ12.7, 3.3 Hz, 1H, 3-H), 3.97
(dd, Jˆ12.7, 5.1 Hz, 1H, 3-H), 4.20 (dt, Jˆ5, 3.1 Hz, 1H, 4-
Hax), 5.07 and 5.20 (2d, Jˆ12.5 Hz, 1H each, CH2Ph), 6.14
(d, Jˆ10.3 Hz, 1H, 7-H), 6.93 (d, Jˆ10.3 Hz, 1H, 8-H),
7.24±7.36 (m, 7H, PhH), 7.91 (d, Jˆ8.4 Hz, 2H, Ts-o-H);
MS, m/z (rel intensity) 583 (M1, 0.03), 526 (7), 228 (11), 91
(100), 73 (20). Anal. Calcd for C30H37NO7SSi: C, 61.72; H,
6.39; N, 2.4; S, 5.49. Found: C, 61.66; H, 6.36; N, 2.43; S,
With dihydropyridone 12b. Method A: From 12b (500 mg,
1.73 mmol) and diene 1 (0.7 ml, 3.5 mmol) in p-cymene
(8 ml) for 5 h, and then from CSA (140 mg, 0.6 mmol) in

4036
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
5.38. Method B: From 16a (300 mg, 0.58 mmol) and diene 1
(0.34 ml, 1.74 mmol) in C6H6 (10 ml) for 1 h, adducts 20a
(one diastereomer of unknown con®guration at C-8, accom-
panied by a minor diastereomer of unknown con®guration,
4:1, 132 mg, 40%) and 21a (46 mg, 13%) were obtained
after chromatography (9:1 hexane±AcOEt). (4S,4aR,8aR)-
8a-(Benzyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
1,6-dioxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,6,8a-octahy-
droisoquinoline (21a): 1H NMR (200 MHz) 0.07 and 0.11
(2s, 3H each, Me2Si), 0.90 (s, 9H, t-Bu), 2.30 (dd, Jˆ16.8,
5 Hz, 1H, 5-H), 2.41 (s, 3H, Me-Ts), 2.62 (dd, Jˆ16.8,
5.2 Hz, 1H, 5-H), 2.92 (dt, Jˆ9.2, 5.2 Hz, 1H, 4a-H), 3.51
(dd, Jˆ12, 8.5 Hz, 1 H, 3-Hax), 3.88 (td, Jˆ8.7, 4.7 Hz, 1H,
4-Hax), 4.22 (dd, Jˆ12, 4.8 Hz, 1H, 3-Heq), 5.07 (s, 2H,
CH2Ph), 6.17 (d, Jˆ10.2 Hz, 1H, 7-H), 6.75 (d, Jˆ10.2 Hz,
1H, 8-H), 7.10±7.40 (m, 7H, PhH), 7.88 (d, Jˆ8.4 Hz, 2H,
Ts-o-H). Method C: From 16a (70 mg, 0.13 mmol) in
CH2Cl2 (2 ml), ZnBr2 (30 mg, 0.13 mmol) in CH2Cl2
(2 ml), and diene 1 (0.07 ml, 0.41 mmol) at 258C for 4 h,
adducts 20a (one diastereomer of unknown con®guration at
C-8, accompanied by traces of the same minor diastereomer
as in Method B, 17 mg, 20%) were obtained after chroma-
tography (9:1 hexane±AcOEt).
1,6-dioxo-1,2,3,4,4a,5,6,8a-octahydroisoquinoline (22b):
1H NMR (300 MHz) -0.02 and 0.02 (2s, 3H each, Me2Si),
0.78 (s, 9H, t-Bu), 2.34 (dd, Jˆ17, 6 Hz, 1H, 5-H), 2.65 (dd,
Jˆ17, 6.3 Hz, 1H, 5-H), 3.06 (td, Jˆ5.8, 3.4 Hz, 1H, 4a-H),
3.60 (dd, Jˆ13.4, 2.9 Hz, 3-H), 3.87 (s, 3H, OMe), 3.95 (dd,
Jˆ13.4, 5.1 Hz, 1H, 3-H), 4.19 (dt, Jˆ5.2, 3 Hz, 1H, 4-H),
5.21 and 5.28 (2d, Jˆ12.1 Hz, 1H each, CH2Ph), 6.18 (d,
Jˆ10.3 Hz, 1H, 7-H), 7.07 (d, Jˆ10.3 Hz, 1H, 8-H), 7.35 (s,
5H, PhH). Anal. Calcd for C25H33NO7Si: C, 61.58; H, 6.82;
N, 2.87. Found: C, 61.83; H, 6.95; N, 2.81.
Diels±Alder reactions from 2-methylbuta-1,3-diene (2)
With dihydropyridone 12a. Method C: From 12a (500 mg,
1.29 mmol) in CH2Cl2 (5 ml), ZnBr2 (290 mg, 1.29 mmol)
in CH2Cl2 (10 ml), and diene 2 (0.9 ml, 9.0 mmol) at 258C
for 2.5 h, cis-8a-(benzyloxycarbonyl)-6-methyl-1-oxo-2-
(p-toluenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquino-
line (23a) (390 mg, 65%) was obtained after crystallization
from Et2O: mp 114±1158C (Et2O); IR (KBr) 1750, 1680,
1
1175 cm21; H NMR (200 MHz) 1.56 (s, 3H, 6-Me), 1.72
(m, 1H, 5-H), 1.89 (m, 2H, 4-H), 1.95 (d, Jˆ4.4 Hz, 1H,
5-H), 2.35 (m, 1H, 8-H), 2.41 (s, 3H, MeTs), 2.54 (m, 1H,
8-H), 2.63 (m, 1H, 4a-H), 3.53 (dt, Jˆ12.2, 8.4 Hz, 1H,
3-H), 4.27 (dt, Jˆ12.4, 5.2 Hz, 1H, 3-H), 5.02 and 5.13
(2d, Jˆ12.6 Hz, 1H each, CH2Ph), 5.27 (br s, 1H, 7-H),
7.24 (m, 7H, PhH and Ts-m-H), 7.85 (d, Jˆ8.4 Hz, 2H,
Ts-o-H); MS, m/z (rel intensity) 453 (M1, 1), 320 (17),
319 (73), 254 (17), 190 (13), 119 (17), 91 (100). Anal.
Calcd for C25H27O5NS´1/2H2O: C, 64.92; H, 6.01; N,
3.03; S, 6.93. Found: C, 64.60; H, 5.88; N, 3.31; S, 6.93.
With dihydropyridone 16b. Method B: From 16b (311 mg,
0.74 mmol) and diene 1 (0.28 ml, 1.47 mmol) in C6H6
(6 ml) for 2 h, and then from CSA (17 mg, 0.07 mmol) in
THF (6 ml) at re¯ux for 2.5 h, a mixture of adducts was
obtained after chromatography (9:1 hexane±AcOEt). Crys-
tallization (pentane) gave adduct 21b (40 mg, 11%).
Evaporation of the mother liquor furnished adduct 20b
(one diastereomer of unknown con®guration at C-8, accom-
panied by traces of a minor diastereomer, 100 mg, 29%).
(4S,4aR,8aS)-8a-(Benzyloxycarbonyl)-4-(tert-butyldi-
methylsilyloxy)-8-methoxy-2-(methoxycarbonyl)-1,6-di-
oxoperhydroisoquinoline (20b): 1H NMR (200 MHz) 0.01
and 0.05 (2s, 3H each, Me2Si), 0.83,(s, 9H, t-Bu), 2.05 (dd,
Jˆ15, 6.6 Hz, 1H, 5-H), 2.63 (m, 2H, 5-H and 7-H), 2.80
(m, 1H, 4a-H), 2.89 (dd, Jˆ16, 3.6 Hz, 1H, 7-H), 3.20 (s,
3H, OMe), 3.22 (dd, Jˆ12.4, 9.6 Hz, 1H, 3-Hax), 3.82 (s,
3H, CO2Me), 3.96 (dd, Jˆ12.4, 5.4 Hz, 1H, 3-Heq), 4.20
(ddd, Jˆ11, 9.2, 5.2 Hz, 1H, 4-H), 4.42 (m, 1H, 8-H), 5.13
and 5.21 (2d, Jˆ12.8 Hz, 1H each, CH2Ph), 7.29 (s, 5H,
PhH). Anal. Calcd for C26H37NO8Si: C, 60.09; H, 7.18; N,
2.70. Found: C, 60.16; H, 7.26; N, 2.78. (4S,4aR,8aR)-8a-
(Benzyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-
(methoxycarbonyl)-1,6-dioxo-1,2,3,4,4a,5,6,8a-octahydro-
isoquinoline (21b): mp 122±1248C (n-pentane). IR (KBr)
With dihydropyridone 12b. Method C: From 12b
(500 mg, 1.7 mmol) in CH2Cl2 (5 ml), ZnBr2 (390 mg,
1.73 mmol) in CH2Cl2 (5 ml), and diene 2 (0.86 ml,
8.5 mmol) at 258C for 1.5 h, cis-8a-(benzyloxycarbonyl)-
2-(methoxycarbonyl)-6-methyl-1-oxo-1,2,3,4,4a,5,8,8a-
octahydroisoquinoline (23b) (407 mg, 67%) was obtained
after chromatography (1:1 hexane±AcOEt): IR (NaCl)
1
1775, 1725, 1680 cm21; H NMR (300 MHz) 1.58 (s, 3H,
6-Me), 1.68 (dd, Jˆ17.9, 3.8 Hz, 1H, 5-H), 1.80 (m, 2H,
4-H), 1.95 (ddd, Jˆ18.3, 3.3, 0.8 Hz, 1H, 5-H), 2.49 (dm,
Jˆ17.3 Hz, 1H, 8-H), 2.68 (m, 3H, 8-H and 4a-H), 3.45 (dt,
Jˆ12.6, 5.4 Hz, 1H, 3-H), 3.81 (s, 3H, OMe), 3.95 (dt,
Jˆ13, 4.8 Hz, 1H, 3-H), 5.10 and 5.22 (2d, Jˆ12.3 Hz,
1H each, CH2Ph), 5.32 (br s, 1H, 7-H), 7.31 (s, 5H, PhH).
Anal. Calcd for C20H23NO5´1/2H2O: C, 65.56; H, 6.60; N,
3.82. Found: C, 65.54; H, 6.45; N, 4.10.
1
1743, 1726, 1711, 1687 cm21; H NMR (200 MHz) 0.05
and 0.06 (2s, 3H, Me2Si), 0.89 (s, 9H, t-Bu), 2.35 (dd,
Jˆ17, 5.2 Hz, 1H, 5-H), 2.67 (dd, Jˆ17, 4.6 Hz, 1H,
5-H), 3.01 (dtd, Jˆ8.8, 4.6, 1.5 Hz, 1H, 4a-H), 3.43 (dd,
Jˆ12.4, 8.8 Hz, 3-Hax), 3.84, (ddd, Jˆ8.8, 4.8 Hz, 1H,
4-H), 3.89 (s, 3H, OMe), 4.00 (dd, Jˆ12.4, 4.8 Hz, 1H,
3-Heq), 5.24 and 5.28 (2d, Jˆ11 Hz, 1H each, CH2Ph),
6.21 (d, Jˆ10.4 Hz, 1H, 7-H), 6.90 (dd, Jˆ10.3, 1.5 Hz,
1H, 8-H), 7.35 (s, 5H, PhH). Method C: From 16b (200
mg, 0.47 mmol) in CH2Cl2 (4 ml), ZnBr2 (106 mg, 0.47
mmol) in CH2Cl2 (2 ml), and diene 1 (0.27 ml, 1.42
mmol) at 258C for 14 h, adducts 21b (64 mg, 28%) and
22b (44 mg, 19%) were obtained after chromatography
(7:3 hexane±AcOEt). (4S,4aS,8aS)-8a-(Benzyloxycarbo-
nyl)-4-(tert-butyldimethylsilyloxy)-2-(methoxycarbonyl)-
With dihydropyridone 16a. Method C: From 16a (400 mg,
0.77 mmol) in CH2Cl2 (15 ml), ZnBr2 (173 mg, 0.77 mmol)
in CH2Cl2 (8 ml), and diene 2 (0.38 ml, 3.85 mmol) at 08C
for 3 h, adducts 25a (80 mg, 18%) and 27a (239 mg, 52%)
were obtained after chromatography (CH2Cl2). (4S,4aR,
8aR)-8a-(Benzyloxycarbonyl)-4-(tert-butyldimethylsilyl-
oxy)-6-methyl-1-oxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,8,
8a-octahydroisoquinoline (25a): 1H NMR (300 MHz) 0.09
and 0.15 (2s, 3H each, Me2Si), 0.93 (s, 9H, t-Bu), 1.61 (s,
3H, 6-Me), 1.75 (dm, Jˆ18.2 Hz, 1H, 5-H), 2.07 (dm, Jˆ
18.1 Hz, 1H, 5-H), 2.29 (dm, Jˆ18.1 Hz, 1H, 8-H), 2.44 (s,
3H, MeTs), 2.58 (ddd, Jˆ9, 5.8, 3.5 Hz, 1H, 4a-H), 2.76
(dm, Jˆ18.2 Hz, 1H, 8-H), 3.35 (dd, Jˆ12, 9 Hz, 1H,
3-Hax), 3.97 (td, Jˆ9, 6.2 Hz, 1H, 4-Hax), 4.39 (dd,

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4037
Jˆ12, 6.2 Hz, 1H, 3-Heq), 5.04 and 5.11 (2d, Jˆ12.4 Hz,
1H each, CH2Ph), 5.37 (br s, 1H, 7-H), 7.17 (m, 2H, PhH),
7.28±7.34 (m, 5H, PhH), 7.88 (d, Jˆ8.4 Hz, 2H, Ts-o-H).
(4S,4aS,8aS)-isomer (27a): mp 108±1108C (pentane);
[a]2D0ˆ135.3 (c 1, CHCl3); IR (KBr) 1750, 1688, 1354,
Diels±Alder reactions from 2,3-dimethylbuta-1,3-diene
(3)
With dihydropyridone 12a. Method A: From 12a (500 mg,
1.29 mmol) and diene 3 (0.7 ml, 6.2 mmol) in p-cymene
(10 ml) for 6 h, adduct 24a (150 mg, 25%) and dihydropyri-
done 10a (50 mg) were obtained after chromatography
(85:15 hexane±AcOEt). cis-8a-(Benzyloxycarbonyl)-6,7-
dimethyl-1-oxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,8,8a-
octahydroisoquinoline (24a): mp 115±1178C (Et2O); IR
1
1176 cm21; H NMR (200 MHz) 0.00 and 0.02 (2s, 3H
each, Me2Si), 0.89 (s, 9H, t-Bu), 1.55 (s, 3H, 6-Me), 1.73
(dd, Jˆ19.4, 9.2 Hz, 1H, 5-H), 2.06 (dd, Jˆ18.2, 6.6 Hz,
1H, 5-H), 2.30 (dm, Jˆ17.2 Hz, 1H, 8-H), 2.43 (s, 3H,
MeTs), 2.67 (ddd, Jˆ10, 6.6, 4.4 Hz, 1H, 4a-H), 2.83
(dm, Jˆ17.2 Hz, 1H, 8-H), 3.77 (dd, Jˆ12.8, 7 Hz, 1H,
3-H), 3.85 (dd, Jˆ12.6, 6 Hz, 1H, 3-H), 4.12 (td, Jˆ6.5,
4.8 Hz, 1H, 4-Heq), 4.99 and 5.24 (2d, Jˆ12 Hz, 1H each,
CH2Ph), 5.27 (br s, 1H, 7-H), 7.25±7.45 (m, 7H, PhH), 7.89
(d, Jˆ8.6 Hz, 2H, Ts-o-H); MS, m/z (rel intensity) 91 (100),
448 (21), 526 (6). Anal. Calcd for C31H41NO6SiS: C, 63.78;
H, 7.08; N, 2.4; S, 5.49. Found: C, 63.80; H, 7.16; N, 2.39;
S, 5.30.
1
(KBr) 1736, 1691, 1362, 1170 cm21; H NMR (300 MHz)
1.52 and 1.59 (2s, 3H each, 6- and 7-Me), 1.75 (dm, Jˆ
19 Hz, 1H, 5-H), 1.82±1.91 (m, 2H, 4-H), 1.97 (dm, Jˆ
19 Hz, 1H, 5-H), 2.34 (d, Jˆ17 Hz, 1H, 8-H), 2.40 (s, 3H,
MeTs), 2.48 (d, Jˆ17 Hz, 1H, 8-H), 2.59 (qn, Jˆ7 Hz, 1H,
4a-H), 3.53 (dt, Jˆ12, 8 Hz, 1H, 3-H), 4.26 (dt, Jˆ12, 5 Hz,
1H, 3-H), 5.03 and 5.08 (2d, Jˆ12.4 Hz, 1H each, CH2Ph),
7.13±7.20 (m, 2H, PhH), 7.23±7.34 (m, 5H, PhH), 7.85 (d,
Jˆ8.5 Hz, 2H, Ts-o-H); MS, m/z (rel intensity) 467 (M1, 1),
333 (12), 332 (56), 176 (10), 133 (16), 91 (100), 65 (13).
Anal. Calcd for C26H29O5NS: C, 66.79; H, 6.25; N, 3.00; S,
6.86. Found: C, 66.70; H, 6.30; N, 3.00; S, 6.76. Method C:
From 12a (300 mg, 0.77 mmol) in CH2Cl2 (5 ml), ZnBr2
(178 mg, 0.77 mmol) in CH2Cl2 (5 ml), and diene 3 (0.4
ml, 3.5 mmol) at 258C for 2.5 h, adduct 24a (250 mg,
69%) was obtained after crystallization from Et2O.
X-Ray crystal structure of 27a. Crystal data:
C31H41NO6SSi, orthorhombic, space group P212121, aˆ
Ê
Ê
Ê
9.880 (2) A, bˆ10.300 (1) A, cˆ31.694 (6) A, Vˆ3225.3
(9) A , Zˆ4, m (MoKa)ˆ0.178 mm21, Dcˆ1.202 mg m23
.
Ê 3
The experiment was done on an Enraf±Nonius CAD4
diffractometer using graphite monochromated MoKa
radiation. The crystal had approximate dimensions of
0.52£0.45£0.15 mm. Data collection was up to a resolution
of 2uˆ49.96 8 producing 3310 re¯ections. The structure
was solved by direct methods (shelxs 86) after applying
Lorentz, polarization and absorption (empirical psi scan
method) corrections to the 3229 independent re¯ections.
Full matrix least-squares re®nement (shelxl 93) using
anisotropic thermal parameters for non-H atoms and a
global isotropic temperature factor for the H-atoms (intro-
duced at calculated positions) converged to a R factor of
0.136 (0.057 for re¯ections with I.2s(I)). Maximum
and minimum heights at the ®nal difference Fourier
With dihydropyridone 12b. Method A: From 12b (500 mg,
1.73 mmol) and diene 3 (0.7 ml, 6.2 mmol) in p-cymene
(5 ml) for 2 h, adduct 24b (74 mg, 11%) was obtained
after column chromatography (hexane±AcOEt, increasing
polarity). cis-8a-(Benzyloxycarbonyl)-2-(methoxycarbo-
nyl)-6,7-dimethyl-1-oxo-1,2,3,4,4a,5,8,8a-octahydroiso-
1
quinoline (24b): IR (NaCl) 1777, 1747, 1726 cm21; H
NMR (300 MHz) 1.56 and 1.63 (2s, 3H each, 6- and
7-Me), 1.80 (m, 2H, 4-H), 2.01 (dm, Jˆ13.5 Hz, 2H,
5-H), 2.47 and 2.58 (2d, Jˆ17 Hz, 1H each, 8-H), 2.68
(dq, Jˆ8.4, 5.5 Hz, 1H, 4a-H), 3.45 (ddd, Jˆ13, 10,
3.6 Hz, 1H, 3-Hax), 3.84 (s, 3H, OMe), 3.98 (ddd, Jˆ
13.3, 6, 4 Hz, 1H, 3-Heq), 5.14 and 5.22 (2d, Jˆ12 Hz,
1H each, CH2Ph), 7.32 (m, 5H, PhH). Anal. Calcd for
C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C, 67.75;
H, 6.89; N, 3.61. Method C: From 12b (1 g, 3.46 mmol) in
CH2Cl2 (15 ml), ZnBr2 (780 mg, 3.46 mmol) in CH2Cl2
(5 ml), and diene 3 (2.3 ml, 20.4 mmol) at 258C for 2 h,
adduct 24b (946 mg, 73%) was obtained after chroma-
tography (1:1 hexane±AcOEt).
Ê 23
synthesis were 0.31 and 20.29 e A . Complete data have
been deposited at the Cambridge Crystallographic Data
Centre.
With dihydropyridone 16b. Method C: From 16b
(300 mg, 0.71 mmol) in CH2Cl2 (12 ml), ZnBr2 (160 mg,
0.71 mmol) in CH2Cl2 (6 ml), and diene 2 (0.36 ml,
3.57 mmol) at 08C for 2 h, a mixture of adducts 25b and
27b (1:6, 288 mg, 82%) was obtained after chromatography
(8:2 hexane±AcOEt). An analytical sample of (4S,4aS,
8aS)-8a-(benzyloxycarbonyl)-4-(tert-butyldimethylsilyl-
oxy)-2-(methoxycarbonyl)-6-methyl-1-oxo-1,2,3,4,4a,5,8,
8a-octahydroisoquinoline (27b) was obtained by chroma-
tography (8:2 hexane±AcOEt): [a]2D0ˆ170.4 (c 1, CHCl3);
With dihydropyridone 16a. Method C: From 16a (400 mg,
0.77 mmol) in CH2Cl2 (15 ml), ZnBr2 (173 mg, 0.77 mmol)
in CH2Cl2 (8 ml), and diene 3 (0.61 ml, 5.39 mmol) at 08C
for 3 h, adducts 26a (126 mg, 27%) and 28a (253 mg, 55%)
were obtained after chromatography (9:1 hexane±AcOEt).
(4S,4aR,8aR)-8a-(Benzyloxycarbonyl)-4-(tert-butyldimethyl-
silyloxy)-6,7-dimethyl-2-(p-toluenesulfonyl)-1-oxo-1,2,3,
4,4a,5,8,8a-octahydroisoquinoline (26a): IR (NaCl) 1739,
1699, 1361, 1172 cm21; 1H NMR (200 MHz) 0.08 and 0.14
(2s, 3H each, Me2Si), 0.93 (s, 9H, t-Bu), 1.61 and 1.62 (2s,
3H each, 6- and 7-Me), 1.81 (dm, Jˆ18.3 Hz, 1H, 5-H),
2.08 (dm, Jˆ18.2 Hz, 1H, 5-H), 2.28 (dm, Jˆ16.8 Hz,
1H, 8-H), 2.44 (s, 3H, MeTs), 2.53 (m, 1H, 4a-H), 2.64
(dm, Jˆ16.8 Hz, 1H, 8-H), 3.34 (dd, Jˆ12, 8.8 Hz, 1H,
3-Hax), 3.96 (td, Jˆ8.6, 6.2 Hz, 1H, 4-Hax), 4.39 (dd,
1
IR (NaCl) 1782, 1727 cm21; H NMR (200 MHz) 0.00 (s,
6H, Me2Si), 0.86 (s, 9H, t-Bu), 1.66 (s, 3H, Me), 1.88 (dd,
Jˆ18, 10.4 Hz, 1H, 5-H), 2.12 (dd, Jˆ18.4, 6.2 Hz, 1H,
5-H), 2.34 (dm, Jˆ16.8 Hz, 1H, 8-H), 2.77 (ddd, Jˆ10.2,
6.6, 4.4 Hz, 1H, 4a-Heq), 2.98 (ddm, Jˆ17.2, 3.2 Hz, 1H,
8-H), 3.63 (d, Jˆ7 Hz, 2H, 3-H), 3.86 (s, 3H, OMe), 4.13
(td, Jˆ7, 4.1 Hz, 1H, 4-H), 5.10 and 5.32 (2d,
Jˆ12.2 Hz, 1H each, CH2Ph), 5.38 (m, 1H, 7-H), 7.34
(m, 5H, PhH); MS, m/z (rel intensity) 353 (9), 352 (34),
91 (100), 73 (31), 59 (10). Anal. Calcd for C26H37NO6Si´1/
4H2O: C, 63.45; H, 7.68; N, 2.85. Found: C, 63.19; H, 7.71;
N, 3.02.

4038
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
Jˆ12, 6.2 Hz, 1H, 3-Heq), 5.06 (s, 2H, CH2Ph), 7.12±7.39
(m, 7H, PhH), 7.88 (d, Jˆ8.3 Hz, 2H, Ts-o-H). Anal. Calcd
for C32H43NO6SSi´1/4H2O: C, 63.81; H, 7.28; N, 2.33; S,
5.32. Found: C, 63.70; H, 7.53; N, 2.31; S, 4.88. MS, m/z (rel
intensity) 599 (M111, 42), 598 (M1, 100), 91 (64).
(4S,4aS,8aS)-Isomer (28a): IR (NaCl) 1740, 1704, 1362,
6.86. Found: C, 66.61; H, 6.32; N, 3.05; S, 6.95. Method C:
From 12a (500 mg, 1.29 mmol) in CH2Cl2 (5 ml), ZnBr2
(290 mg, 1.3 mmol) in CH2Cl2 (10 ml), and diene 4 (commer-
cial mixture of isomers, 0.8 ml, 9.1 mmol) at 258C for 2.5 h,
adduct 29a (430 mg, 70%, the same diastereomer of unknown
con®guration at C-5 and C-8 obtained by method A) was
obtained after crystallization from Et2O.
1
1171 cm21; H NMR (300 MHz) 0.00 (s, 6H, Me2Si), 0.87
(s, 9H, t-Bu), 1.52 (s, 6H, 6- and 7-Me), 1.81 (ddm, Jˆ18.2,
8 Hz, 1H, 5-H), 2.06 (ddm, Jˆ18.2, 6.8 Hz, 1H, 5-H), 2.29
(dm, Jˆ16.4 Hz, 1H, 8-H), 2.42 (s, 3H, MeTs), 2.62
(ddd, Jˆ9.5, 7, 4.4 Hz, 1H, 4a-H), 2.68 (dm, Jˆ
15.9 Hz, 8-H), 3.78 (dd, Jˆ12.4, 6.8 Hz, 1H, 3-H),
3.84 (dd, Jˆ12.5, 5.9 Hz, 1H, 3-H), 4.13 (td, Jˆ6.2,
4.6 Hz, 1H, 4-Heq), 5.00 and 5.18 (2d, Jˆ12 Hz, 1H
each, CH2Ph), 7.20±7.40 (m, 7H, PhH), 7.89 (d, Jˆ
8.4 Hz, 2H, Ts-o-H). Anal. Calcd for C32H43NO6SSi´1/
2H2O: C, 63.34; H, 7.31; N, 2.31; S, 5.28. Found: C, 63.12;
H, 7.41; N, 2.31; S, 4.82.
With dihydropyridone 12b. Method C: From 12b
(300 mg, 1.03 mmol) in CH2Cl2 (5 ml), ZnBr2 (230 mg,
1.03 mmol) in CH2Cl2 (5 ml), and diene 4 (commercial
mixture of isomers, 0.8 ml, 7.21 mmol) at 258C for 7 h,
cis-8a-(benzyloxycarbonyl)-2-(methoxycarbonyl)-5,8-di-
methyl-1-oxo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (29b)
(255 mg, 63%, 1:1 mixture of two diastereomers of
unknown con®guration at C-5 and C-8) was obtained after
chromatography (1:1 hexane±AcOEt). Analytical samples
of both diastereomers were obtained by chromatography
(1:1 hexane±AcOEt). Less polar diastereomer of 29b: IR
1
With dihydropyridone 16b. Method C: From 16b (200 mg,
0.47 mmol) in CH2Cl2 (10 ml), ZnBr2 (106 mg, 0.47 mmol)
in CH2Cl2 (2 ml), and diene 3 (0.26 ml, 2.37 mmol) at 08C
for 3 h, a mixture of adducts 26b and 28b (1:3, 175 mg,
75%) was obtained after chromatography (8:2 hexane±
AcOEt). An analytical sample of (4S,4aS,8aS)-8a-(benzyl-
oxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(methoxy-
carbonyl)-6,7-dimethyl-1-oxo-1,2,3,4,4a,5,8,8a-octahydro-
isoquinoline (28b) was obtained by chromatography (8:2
hexane±AcOEt): [a]2D0ˆ115.8 (c 0.4, CHCl3); IR (NaCl)
1781, 1726 cm21; 1H NMR (200 MHz) 0.00 (s, 6H, Me2Si),
0.87 (s, 9H, t-Bu), 1.62 and 1.64 (2s, 3H each, 6- and 7-Me),
1.92 (ddm, Jˆ18.2, 10 Hz, 1H, 5-H), 2.12 (dd, Jˆ18.2,
6.3 Hz, 1H, 5-H), 2.35 (dm, Jˆ16.2 Hz, 1H, 8-H), 2.72
(ddd, Jˆ10.2, 7, 4.4 Hz, 1H, 4a-H), 2.84 (d, Jˆ16.6 Hz,
1H, 8-H), 3.63 (d, Jˆ7 Hz, 2H, 3-H), 3.87 (s, 3H, OMe),
4.13 (td, Jˆ7, 4.4 Hz, 1H, 4-H), 5.13 and 5.32 (2d,
Jˆ12 Hz, 1H each, CH2Ph), 7.37 (m, 5H, PhH); MS, m/z
(rel intensity) 366 (100), 115 (10), 91 (69), 73 (78), 59 (18).
Anal. Calcd for C27H39NO6Si´H2O: C, 62.40; H, 7.95; N,
2.70. Found: C, 62.86; H, 7.83; N, 2.72.
(NaCl) 1775, 1727, 1702 cm21; H NMR (300 MHz) 0.92
(d, Jˆ7.4 Hz, 3H, 5-Me), 1.12 (d, Jˆ7.6 Hz, 3H, 8-Me),
1.73 (m, 2H, 4-H), 1.96 (m, 1H, 5-H), 2.49±2.60 (m, 1H,
4a-H), 3.30 (m, 1H, 8-H), 3.59 (m, 1H, 3-Hax), 3.85 (s, 3H,
OMe), 3.95 (dt, Jˆ12.6, 3.2 Hz, 1H, 3-Heq), 5.06 and 5.26
(2d, Jˆ12.4 Hz, 1H each, CH2Ph), 5.26±5.29 (m, 1H, 6-H),
5.58 (ddd, Jˆ10.4, 3.5, 3 Hz, 1H, 7-H), 7.31 (s, 5H, PhH);
MS, m/z (rel intensity) 232 (47), 214 (31), 188 (31), 91
(100), 65 (22), 55 (11). Anal. Calcd for C21H25NO5: C,
67.91; H, 6.78; N, 3.77. Found: C, 67.33; H, 7.34; N,
3.11. More polar diastereomer of 29b: IR (NaCl) 1775,
1
1729, 1703 cm21; H NMR (300 MHz) 0.79 (d, Jˆ7.4 Hz,
3H, 5-Me), 1.02 (d, Jˆ7 Hz, 3H, 8-Me), 1.69±1.87 (m, 3H,
4-H and 5-H), 2.19±2.26 (m, 2H, 4-H and 4a-H), 3.08 (ddd,
Jˆ14.3, 8, 6 Hz, 1H, 3-Hax), 3.20 (m, 1H, 8-H), 3.84 (s, 3H,
OMe), 4.1 (ddd, Jˆ14.3, 8, 4 Hz, 1H, 3-Heq), 5.18 (s, 2H,
CH2Ph), 5.34 (dm, Jˆ10 Hz, 1H, 6-H), 5.65 (ddd, Jˆ10, 5,
2.5 Hz, 1H, 7-H), 7.34 (s, 5H, PhH); MS, m/z (rel intensity)
232 (47), 214 (31), 188 (31), 91 (100), 65 (22). Anal. Calcd
for C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C, 67.49;
H, 7.30; N, 3.18.
With dihydropyridone 16a. Method C: From 16a (300 mg,
0.58 mmol) in CH2Cl2 (12 ml), ZnBr2 (130 mg, 0.58 mmol)
in CH2Cl2 (6 ml), and diene 4 (commercial mixture of
isomers, 0.33 ml, 2.9 mmol) at 08C for 4 h, (4S,4aS,8aS)-
8a-(benzyloxycarbonyl)-4-(tert-butyldimethylsilyloxy)-5,
8-dimethyl-2-(p-toluenesulfonyl)-1-oxo-1,2,3,4,4a,5,8,8a-
octahydroisoquinoline (30a) (unknown con®guration at
C-5 and C-8; accompanied by a minor diastereomer of
unknown con®guration, 3.5:1, 256 mg, 73%) was obtained
after chromatography (CH2Cl2). An analytical sample of
30a was obtained by chromatography (CH2Cl2): IR (NaCl)
1780, 1728, 1382 cm21; 1H NMR (300 MHz) 0.00 and 0.02
(2s, 3H each, Me2Si), 0.80 (s, 9H, t-Bu), 0.96 (d, Jˆ7.4 Hz,
3H, 8-Me), 1.05 (d, Jˆ7.6 Hz, 3H, 5-Me), 2.18 (m, 1H,
5-H), 2.36 (s, 3H, MeTs), 2.66, (t, Jˆ5.6 Hz, 1H, 4a-H),
2.99 (m, 1H, 8-H), 3.51 (dd, Jˆ12.6, 6.6 Hz, 1H, 3-H),
4.03 (dd, Jˆ12.7, 5.3 Hz, 1H, 3-H), 4.24 (q, Jˆ5.7 Hz,
1H, 4-H), 5.03 and 5.08 (2d, Jˆ11.3 Hz, 1H each,
CH2Ph), 5.47 and 5.54 (2 dt, Jˆ9.7, 2.7 Hz, 1H each, 6-
and 7-H), 7.20±7.40 (m, 7H, PhH), 7.85 (d, Jˆ8.5 Hz, 2H,
H-o-Ts); MS, m/z (rel intensity) 599 (M11, 42), 598 (M1,
100), 91 (64).
Diels±Alder reactions from hexa-2,4-diene (4)
With dihydropyridone 12a. Method A: From 12a (330 mg,
0.85 mmol) and diene 4 (commercial mixture of isomers,
0.34 ml, 2.97 mmol) in p-cymene (10 ml) for 10 h, adduct
29a (67 mg, 17%, one diastereomer of unknown con®gu-
ration at C-5 and C-8) and dihydropyridones 10a and
12a (traces) were obtained after chromatography (85:15
hexane±AcOEt). cis-8a-(Benzyloxycarbonyl)-5,8-dimethyl-
1-oxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroiso-
quinoline (29a): mp 145±1478C (Et2O); IR (KBr) 1745,
1684, 1352, 1169 cm21; 1H NMR (300 MHz) 0.85 (d,
Jˆ7.8 Hz, 3H, 8-Me), 0.94 (d, Jˆ7.4 Hz, 3H, 5-Me), 1.84
(m, 2H, 4-H), 1.96 (m, 1H, 5-H), 2.43 (s, 3H, MeTs), 2.49
(q, Jˆ5 Hz, 1H, 4a-H), 3.18 (m, 1H, 8-H), 3.74 (td, Jˆ12,
6.5 Hz, 1H, 3-Hax), 4.31 (ddd, Jˆ12, 6, 2 Hz, 1H, 3-Heq),
5.02 and 5.11 (2d, Jˆ8.2 Hz, 1H each, CH2Ph), 5.27 (d,
Jˆ10 Hz, 1H, 7-H), 5.53 (dt, Jˆ10, 3 Hz, 1H, 6-H), 7.18
(m, 2H, PhH), 7.29 (m, 5H, PhH and Ts-o-H), 7.89 (d,
Jˆ8 Hz, 2H, Ts-m-H); MS, m/z (rel intensity) 468 (M111,
1), 332 (40), 322 (12), 268 (24), 155 (17), 133 (19), 91 (100).
Anal. Calcd for C26H29O5NS: C, 66.79; H, 6.25; N, 3.00; S,

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4039
With dihydropyridone 16b. Method C: From 16b
(200 mg, 0.47 mmol) in CH2Cl2 (8 ml), ZnBr2 (106 mg,
0.47 mmol) in CH2Cl2 (4 ml), and diene 4 (commercial
mixture of isomers, 0.27 ml, 2.38 mmol) at 08C for 5 h,
after a second addition of the diene (2.5 equiv.) at 258C
for 1 h, (4S,4aS,8aS)-8a-(benzyloxycarbonyl)-4-(tert-butyl-
dimethylsilyloxy)-5,8-dimethyl-2-(methoxycarbonyl)-1-oxo-
1,2,3,4,4a,5,8,8a-octahydroisoquinoline (30b) (unknown
con®guration at C-5 and C-8; accompanied by traces of a
diastereomer of unknown con®guration, 160 mg, 67%) was
obtained after chromatography (4:1 hexane±AcOEt). An
analytical sample of 30b was obtained by chromatography
(4:1 hexane±AcOEt): IR (NaCl) 1780, 1727 cm21; 1H
NMR (200 MHz) 0.05 (s, 6H, Me2Si), 0.85 (s, 9H, t-Bu),
1.05 and 1.15 (2d, Jˆ7.5 Hz, 3H each, 5- and 8-Me), 2.20
(m, 1H, 5-H), 2.77 (t, Jˆ5.5 Hz, 1H, 4a-H), 3.11 (m, 1H,
8-H), 3.50 (dd, Jˆ13.6, 7 Hz, 1H, 3-H), 3.85 (s, 3H,
CO2Me), 3.86 (dd, Jˆ13.6, 5.2 Hz, 1H, 3-H), 4.19 (dt, Jˆ
6.8, 5.2 Hz, 1H, 4-H), 5.10 and 5.31 (2d, Jˆ12.6 Hz, 1H each,
CH2Ph), 5.49 and 5.62 (2dt, Jˆ10, 2.6 Hz, 1H, 6- and 7-H),
7.33 (s, 5H, PhH). Anal. Calcd for C27H39NO6Si´1/2H2O: C,
63.5; H, 7.89; N, 2.74. Found: C, 63.2; H, 7.7; N, 2.66.
(33 mg, 5%) and endo-31b (30 mg, 4%) were obtained
after column chromatography (hexane±AcOEt, increasing
polarity). (4aRS,8SR,8aRS)-8-Acetoxy-8a-(benzyloxycar-
bonyl)-2-(methoxycarbonyl)- 1-oxo-1,2,3,4,4a,5,8,8a-octa-
hydroisoquinoline (exo-31b): IR (KBr) 1760, 1735,
1731 cm21 1H NMR (300 MHz) 1.64 (m, 1H, 4-Heq),
;
1.70 (s, 3H, MeCO), 1.91 (ddm, Jˆ18, 11.5 Hz, 1H,
5-Hax), 2.30 (dt, Jˆ18, 5.5 Hz, 1H, 5-Heq), 2.39 (ddd, Jˆ
14, 7.4, 4.4 Hz, 1H, 4-Hax), 2.90 (m, 1H, 4a-H), 3.21 (ddd,
Jˆ14.3, 8, 4.4 Hz, 1H, 3-Hax), 3.84 (s, 3H, OMe), 4.15
(ddd, Jˆ14.3, 8.7, 7.2 Hz, 1H, 3-Heq), 5.10 and 5.20 (2d,
Jˆ12 Hz, 1H each, CH2Ph), 5.86 (m, 1H, 6-H), 5.93 (m, 1H,
7-H), 5.98 (d, Jˆ4.6 Hz, 1H, 8-H), 7.33 (s, 5H, PhH). Anal.
Calcd for C21H23NO7: C, 62.84; H, 5.78; N, 3.49. Found: C,
62.70; H, 5.93; N, 3.39. (4aRS,8RS,8aRS)-Isomer (endo-
1
31b): IR (KBr) 1775, 1736, 1706 cm21; H NMR (300
MHz) 1.68 (dm, Jˆ14 Hz, 1H, 4-Heq), 1.96 (s, 3H,
MeCO), 2.02 (m, 2H, 5-H), 2.36 (dq, Jˆ13, 6 Hz, 1H, 4-
H), 2.75 (dq, Jˆ13, 4.4 Hz, 1H, 4a-H), 3.66 (td, Jˆ13, 6 Hz,
1H, 3-Hax), 3.87 (s, 3H, OMe), 3.97 (ddd, Jˆ13, 6, 2 Hz,
1H, 3-Heq), 5.13 and 5.27 (d, Jˆ12 Hz, 1H each, CH2Ph),
5.83 (dt, Jˆ10, 4 Hz, 1H, 6-H), 5.93 (dm, Jˆ10 Hz, 1H,
7-H), 5.97 (dd, Jˆ4.2 Hz, allylic J, 1H, 8-H), 7.33 (m,
5H, PhH). Anal. Calcd for C21H23NO7´1/2H2O: C, 61.46;
H, 5.89; N, 3.41. Found: C, 61.6; H, 57.3; N, 3.48. Method
C: From 12b (500 mg, 1.73 mmol) in CH2Cl2 (5 ml), ZnBr2
(389 mg, 1.73 mmol) in CH2Cl2 (5 ml), and diene 5 (1:1
cis±trans mixture, 0.65 ml, 6.06 mmol) at 258C for 3.5 h,
adducts exo-31b (80 mg, 11%) and endo-31b (134 mg,
20%) and aldehyde 34b (86 mg, 14%) were obtained after
chromatography (7:3 hexane±AcOEt). trans-3-(Benzyloxy-
carbonyl)-1-(methoxycarbonyl)-4-[4-oxo-2(E)-butenyl]-
2-piperidone (34b): IR (NaCl) 1772, 1727, 1689 cm21; 1H
NMR (300 MHz) 1.55 (dtd, Jˆ14.1, 10.4 and 4.8 Hz, 1H,
5-Hax), 2.06 (dq, Jˆ14.1 and 4.5 Hz, 1H, 5-Heq), 2.29 (m,
1H, 10-H), 2.39 (m, 1H, 10-H), 2.54 (m, 1H, 4-H), 3.33 (d,
Jˆ9.9 Hz, 1H, 3-H), 3.61 (ddd, Jˆ13.2, 10.7, 4.1 Hz, 1H,
6-Hax), 3.87 (s, 3H, OMe), 3.90 (dt, Jˆ13.2, 4.8 Hz, 1H,
6-Heq), 5.16 and 5.24 (2d, Jˆ12.1 Hz, 1H each, CH2Ph),
6.09 (ddt, Jˆ15.6, 7.7, 1.2 Hz, 1H, 30-H), 6.66 (ddd,
Jˆ15.3, 8.1, 6.8 Hz, 1H, 20-H), 7.35 (m, 5H, PhH), 9.46
(d, Jˆ7.7 Hz, 1H, CHO); 13C NMR (75 MHz) 27.1 (C-5),
35.1 (C-4), 37.4 (C-10), 44.7 (C-6), 54.3 (OMe), 57.4 (C-3),
67.6 (CH2Ph), 128.5 and 128.6, (C-Ph), 131.0 (C-i-Bn),
135.4 (C-30), 150.8 (CO2Me), 152.4 (C-20), 166.4 and
168.7 (CO2Bn and C-2), 193.1 (CHO). MS, m/z (rel inten-
sity) 224 (25); 156 (54); 124 (16); 91 (100); 65 (12). Anal.
Calcd for C19H21O6N´1/3H2O: C, 62.47; H, 5.98; N, 3.83.
Found: C, 62.53; H, 6.09; N, 3.52. Method D: A solution of
12b (300 mg, 1.03 mmol) and diene 5 (1:1 cis±trans
mixture, 0.23 ml, 1.03 mmol) in anhydrous CH2Cl2 (10
ml) cooled at 2208C was added to a solution of EtAlCl2
(1 M in hexane, 0.5 ml) in anhydrous CH2Cl2 (5 ml) at the
same temperature. The mixture was stirred at 2208C for
15 min and then allowed to rise to 08C. More EtAlCl2
(1 M in hexane, 1.5 ml) in anhydrous toluene was added,
and stirring was continued at 08C for 1 h and at 258C for
30 min. After addition of H2O and evaporation of the
organic solvent, the residue was extracted with AcOEt.
Concentration of the dried organic extracts afforded adducts
exo-31b (36 mg, 9%) and endo-31b (240 mg, 58%)
after column chromatography (hexane±AcOEt, increasing
polarity).
Diels±Alder reactions from 1-acetoxybuta-1,3-diene (5)
With dihydropyridone 12a. Method A: From 12a (500 mg,
1.29 mmol) and diene 5 (1:1 cis±trans mixture, 0.53 ml,
4.5 mmol) in p-cymene (15 ml) for 5 h, adducts endo-31a
(51 mg, 8%) and exo-31a (190 mg, 30%) and dihydropyri-
done 10a (traces) were obtained after chromatography (4:1
hexane±AcOEt). (4aRS,8RS,8aRS)-8-Acetoxy-8a-(benzyl-
oxycarbonyl)-1-oxo-2-(p-toluenesulfonyl)-1,2,3,4,4a,5,8,8a-
octahydroisoquinoline (endo-31a): mp 150±1518C (Et2O);
IR (KBr) 1747, 1688, 1358, 1171 cm21; 1H NMR (200 MHz)
1.70 (s, 3H, MeCO), 1.75 (m, 1H, 4-H), 2.00 (m, 2H, 5-H),
2.41 (s, 3H, MeTs), 2.43 (m, 1H, 4-H), 2.68 (dq, Jˆ13.5,
3.7 Hz, 1H, 4a-H), 3.81 (td, Jˆ12, 5.4 Hz, 1H, 3-Hax),
4.20 (ddd, Jˆ12, 6, 1.5 Hz, 1H, 3-Heq), 5.04 and 5.10 (2d,
Jˆ12 Hz, 1H each, CH2Ph), 5.75±5.90 (m, 3H, 6-H, 7-H and
8-Heq), 7.14±7.38 (m, 7H, PhH), 7.92 (d, Jˆ8.4 Hz, 2H,
Ts-o-H); MS, m/z (rel intensity) 135 (10); 238 (10); 105
(12); 92 (10); 91 (100); 69 (13); 65 (13); 57 (17); 55 (19).
Anal. Calcd for C26H27O7NS´1/2H2O: C, 61.65; H, 5.57; N,
2.77; S, 6.33. Found: C, 61.55; H, 5.44; N, 2.78; S, 6.98.
(4aRS,8SR,8aRS)-Isomer (exo-31a): IR (NaCl) 1739,
1
1730, 1713, 1359, 1170 cm21; H NMR (200 MHz) 1.65±
1.85 (m, 2H, 4-H), 1.71 (s, 3H, MeCO), 2.17 (m, 1H, 5-H),
2.32 (m, 1H, 5-H), 2.40 (s, 3H, MeTs), 2.78 (m, 1H, 4a-H),
3.16 (ddd, Jˆ14, 9.5, 7.1 Hz, 1H, 3-Hax), 4.24 (ddd, Jˆ14,
8.5, 3.4 Hz, 1H, 3-Heq), 4.90 and 4.97 (2d, Jˆ12 Hz, 1H
each, CH2Ph), 5.70±5.74 (m, 2H, 6-H and 7-H), 5.79 (d,
Jˆ2.9 Hz, 1H, 8-Heq), 7.15±7.35 (m, 7H, PhH), 7.79 (d,
Jˆ8.4 Hz, 2H, Ts-o-H); MS, m/z (rel intensity) 320 (19);
346 (13); 91 (100); 65 (13). Method C: From 12a (300 mg,
0.77 mmol) in CH2Cl2 (5 ml), ZnBr2 (173 mg, 0.77 mmol) in
CH2Cl2 (5 ml), and diene 5 (1:1 cis±trans mixture, 0.4 ml,
3.85 mmol) at 258C for 4 h, adducts endo-31a (60 mg, 16%)
and exo-31a (136 mg, 35%) were obtained after
chromatography (7:3 hexane±AcOEt).
With dihydropyridone 12b. Method A: From 12b (500 mg,
1.73 mmol) and diene 5 (1:1 cis±trans mixture, 0.4 ml,
3.46 mmol) in p-cymene (5 ml) for 2 h, adducts exo-31b

4040
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
With dihydropyridone 16a. Method C: From 16a (400 mg,
0.77 mmol) in CH2Cl2 (15 ml), ZnBr2 (173 mg, 0.77 mmol)
in CH2Cl2 (5 ml), and diene 5 (1:1 cis±trans mixture,
0.45 ml, 3.85 mmol) at 08C for 6 h, adduct endo-35a
(accompanied by two minor diastereomers of undetermined
con®guration, 2.8:1, 325 mg, 67%) and aldehydes 38a (86
mg, 19%, 2.9:1 mixture of two diastereomers of unknown
con®guration) were obtained after chromatography (4:1
hexane±AcOEt). An analytical sample of the major dia-
stereomer (4S,4aS, 8R, 8aR)-8-acetoxy-8a-(benzyloxy-
carbonyl)-4-(tert-butyldimethylsilyloxy)-1-oxo-2-(p-tolu-
enesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (endo-
35a) was obtained by chromatography (4:1 hexane±
AcOEt): mp 59±618C (pentane); [a]2D0ˆ28.3 (c 1, CHCl3);
8-H), 7.38 (s, 5H, PhH). Anal. Calcd for C27H37NO8Si: C,
61.00; H, 7.01; N, 2.63. Found: C, 60.74; H, 7.17; N, 2.68.
(4S,4aS,8S,8aR)-Isomer (exo-35b): IR (KBr) 1783, 1737
1
cm21; H NMR (300 MHz) 0.08 and 0.11 (2s, 3H each,
Me2Si), 0.89 (s, 9H, t-Bu), 1.72 (s, 3H, MeCO), 2.02
(ddm, Jˆ18.6, 11.1 Hz, 1H, 5-H), 2.38 (dm, Jˆ19.3 Hz,
1H, 5-H), 2.94 (dt, Jˆ10.7, 6.3 Hz, 1H, 4a-H), 3.54 (dd,
Jˆ13.5, 6.4 Hz, 1H, 3-H), 3.64 (dd, Jˆ13.5, 7 Hz, 1H,
3-H), 3.83 (s, 3H, OMe), 4.58 (br q, Jˆ6.3 Hz, 1H, 4-H),
5.13 and 5.18 (2d, Jˆ12 Hz, 1H each, CH2Ph), 5.95 (m, 3H,
6-H, 7-H and 8-H), 7.33 (s, 5H, PhH). (5S)-3 -(Benzyloxy-
carbonyl)-5-(tert-butyldimethylsilyloxy)-1-(methoxycar-
bonyl)-4-[4-oxo-2(E)-butenyl]-2-piperidone (38b): 1H
NMR (200 MHz) 0.07 (s, 6H, Me2Si), 0.86 (s, 9H, t-Bu),
2.06 (m, 1H, 10-H), 2.27 (m, 1H, 4-H), 2.48 (m, 1H, 10-H),
3.55 (dd, Jˆ14.2, 3 Hz, 1H, 6-H), 3.59 (d, Jˆ10.2 Hz, 1H,
3-H), 3.88 (s, 3H, OMe), 4.09 (masked dd, Jˆ14.4, 3.2 Hz,
1H, 6-H), 4.10 (br s, 1H, 5-H), 5.14 and 5.26 (2d, Jˆ12 Hz,
1H each, CH2Ph), 6.08 (dd, Jˆ15.6, 7.2 Hz, 1H, 30-H), 6.63
(dt, Jˆ15.4, 7.4 Hz, 1H, 20-H), 7.37 (m, 5H, PhH), 9.43 (d,
Jˆ7.6 Hz, 1H, CHO); 13C NMR (50.3 MHz) 24.9 and 24.5
(Me2Si), 17.9 (C±Si), 25.6 (t-Bu), 33.5 (C-10), 41.5 (C-4),
52.3 (C-6), 53.9 (C-3), 54.4 (OMe), 64.7 (C-5), 67.7
(CH2Ph), 128.4, 128.5, and 128.6 (C-Ph), 135.0 (C-i-Bn
and C-20), 153.1 (C-30), 154.7 (CO2Me), 166.2 and 169.4
(C-2 and CO2Bn), 193.2 (CHO).
;
IR (KBr) 1746, 1696, 1355,1171 cm21 1H NMR
(500 MHz) 0.00 and 0.03 (2s, 3H each, Me2Si), 0.88 (s,
9H, t-Bu), 1.85 (s, 3H, MeCO), 1.98 (ddq, Jˆ18.7, 10.5,
2.5 Hz, 1H, 5-Ha), 2.21 (dt, Jˆ18.5, 5.5 Hz, 1H, 5-H), 2.42
(s, 3H, MeTs), 2.69 (dt, Jˆ9.5, 6.5 Hz, 1H, 4a-H), 3.82 (d,
Jˆ6 Hz, 2H, 3-H), 4.17 (q, Jˆ6 Hz, 1H, 4-H), 5.09 and 5.14
(2d, Jˆ12 Hz, 1H each, CH2Ph), 5.74 (m, 3H, 6-H, 7-H and
8-H), 7.20±7.35 (m, 7H, PhH), 7.91 (d, Jˆ8.5 Hz, 2H, Ts-o-
H). Anal. Calcd for C32H41NO8SSi´1/2C5H12: C, 62.42; H,
7.14; N, 2.11; S, 4.83. Found: C, 62.25; H, 7.24; N, 2.37; S,
4.51. An analytical sample of the major aldehyde (5S)-3-
(benzyloxycarbonyl)-5-(tert-butyldimethylsilyloxy)-4-(4-
oxo-2(E)-buten-1-yl)-1-(p-toluenesulfonyl)-2-piperidone
(38a) was obtained by chromatography (4:1 hexane±
X-Ray crystal structure of endo-35b. Crystal data:
C27H37NO8Si, orthorhombic, space group P212121, aˆ
AcOEt): IR (NaCl) 1742, 1693, 1362, 1172 cm21 1H
;
Ê
Ê 3
Ê
Ê
NMR (300 MHz) 0.07 and 0.13 (2s, 3H each, Me2Si),
0.82 (s, 9H, t-Bu), 2.15 (m, 1H, 10-H), 2.41 (s, 3H,
MeTs), 2.42 (m, 2H, 4-H and 10-H), 3.45 (d, Jˆ11 Hz,
1H, 3-H), 3.71 (dd, Jˆ12.2, 1.3 Hz, 1H, 6-H), 4.14 (br s,
1H, 5-H), 4.15 (masked dd, Jˆ12.5, 3 Hz, 1H, 6-H), 5.08
and 5.17 (2d, Jˆ12 Hz, 1H each, CH2Ph), 6.02 (dd, Jˆ15.5,
7.5 Hz, 1H, 30-H), 6.58 (dt, Jˆ15.6, 6.6 Hz, 1H, 20-H),
7.20±7.40 (m, 7H, PhH), 7.90 (d, Jˆ8.3 Hz, 2H, Ts-o-H),
9.40 (d, Jˆ7.7 Hz, 1H, CHO); 13C NMR (50.3 MHz) 24.9
and 24.2 (Me2Si), 17.8 (C±Si), 21.6 (MeTs), 25.6 (t-Bu),
33.0 (C-10), 40.9 (C-4), 52.4 (C-6), 52.9 (C-3), 64.7 (C-5),
67.7 (CH2Ph), 128.4, 128.6, 128.8, and 129.4 (C-Ph), 134.5
(C-i-Bn, C-i-Ts and C-20), 145.2 (C-p-Ts), 152.8 (C-30),
165.1 and 168.6 (C-2 and CO2Bn), 193.0 (CHO).
7.8146 (12) A, bˆ10.578 (2) A, cˆ36.032 (5) A, Vˆ
m ,
2978.5 (7) A , Zˆ4,
(MoKa)ˆ0.124 mm21
Dcˆ
1.186 mg m23. The experiment was done on an Enraf±
Nonius CAD4 diffractometer using graphite monochro-
mated MoKa radiation. The crystal had approximate
dimensions of 0.40£0.16£0.15 mm. Data collection was
up to a resolution of 2u(ˆ47.388. producing 2600 re¯ec-
tions. The structure was solved by direct methods (shelxs
86) after applying Lorentz, polarization and absorption
(empirical psi scan method) corrections to the 2600 inde-
pendent re¯ections. Full matrix least-squares re®nement
(shelxl 93) using anisotropic thermal parameters for non-
H atoms and a global isotropic temperature factor for the
H-atoms (introduced at calculated positions) converged to a
R factor of 0.246 (0.052 for re¯ection with I.2s(I)). Maxi-
mum and minimum heights at the ®nal difference Fourier
With dihydropyridone 16b. Method C: From 16b (300 mg,
0.71 mmol) in CH2Cl2 (6 ml), ZnBr2 (160 mg, 0.71 mmol)
in CH2Cl2 (6 ml), and diene 5 (1:1 cis±trans mixture,
0.42 ml, 3.3 mmol) at 08C for 4 h, a mixture of adducts
endo-35b (140.8 mg, 37%) and exo-35b (35.2 mg, 9%)
and aldehyde 38b (one diastereomer of undetermined
con®guration, 35 mg, 10%) were obtained after chroma-
tography (4:1 hexane±AcOEt). (4S,4aS,8R,8aR)-8-Acet-
oxy-8a-(benzyloxycarbonyl)-4-(tert-butyldimethylsilyl-
oxy)-2-(methoxycarbonyl)-1-oxo-1,2,3,4,4a,5,8,8a-octa-
hydroisoquinoline (endo-35b): mp 116±1188C (pentane);
[a]2D0ˆ125.7 (c 2, CHCl3); IR (KBr) 1747, 1724, 1372
Ê 23
synthesis were 0.23 and 20.21 e A . Complete data have
been deposited at the Cambridge Crystallographic Data
Centre.
Diels±Alder reactions from 1-methoxybuta-1,3-diene (6)
With dihydropyridone 12a. Method A: From 12a (500 mg,
1.29 mmol) and diene 6 (1:1 cis±trans mixture, 0.4 ml,
3.96 mmol) in p-cymene (10 ml) for 2 h, adducts endo-
32a and exo-32a (3:2 mixture, 293 mg, 48%) and dihydro-
pyridone 10a (traces) were obtained after chromatography
(4:1 hexane±AcOEt). Isomer endo-32a was isolated by
crystallization from Et2O. (4aRS,8RS,8aRS)-8a-(Benzyl-
oxycarbonyl)-8-methoxy-1-oxo-2-(p-toluenesulfonyl)-1,2,
3,4,4a,5,8,8a-octahydroisoquinoline (endo-32a): mp 149±
1
cm21; H NMR (500 MHz) 0.00 (s, 6H, Me2Si), 0.87 (s,
9H, t-Bu), 1.98 (s, 3H, MeCO), 2.17 (ddm, Jˆ17.3,
10.3 Hz, 1H, 5-H), 2.32 (ddm, Jˆ18.8, 6.8 Hz, 1H, 5-H),
2.82 (ddd, Jˆ10.3, 6.9, 5.1 Hz, 1H, 4a-H), 3.64 (dd, Jˆ13.3,
7.6 Hz, 1H, 3-H), 3.69 (dd, Jˆ13.3, 6.3 Hz, 1H, 3-H), 3.88
(s, 3H, OMe), 4.17 (br q Jˆ6.3 Hz, 1H, 4-H), 5.16 and 5.28
(2d, Jˆ12 Hz, 1H each, CH2Ph), 5.82 (m, 3H, 6-H, 7-H and
1
1518C (Et2O); IR (KBr) 1737 1682, 1357, 1170 cm21; H
NMR (200 MHz) 1.62 (dm, Jˆ13.4 Hz, 1H, 4-H), 1.93 (m,
2H, 5-H), 2.40 (s, 3H, MeTs), 2.48 (ddd, Jˆ19, 12.3, 7 Hz,

N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4041
1H, 4-H), 2.64 (dm, Jˆ14 Hz, 1H, 4a-H), 2.87 (s, 3H,
OMe), 3.82 (td, Jˆ12, 5.6 Hz, 1H, 3-Hax), 4.09±4.18 (m,
2H, 8-H and 3-Heq), 5.01 and 5.19 (2d, Jˆ12.4 Hz, 1H
each, CH2Ph), 5.70 (dt, Jˆ10.2, 4 Hz, 1H, 6-H), 5.91 (ddt,
Jˆ10.2, 4.3, 2 Hz, 1H, 7-H), 7.21±7.35 (m, 7H, PhH), 7.90
(d, Jˆ8.3 Hz, 2H, Ts-o-H); MS, m/z (rel intensity) 470 (M1,
1); 321 (11); 270 (15); 240 (19); 187 (25); 91 (100); 84 (26);
65 (14). Anal. Calcd for C25H27O6NS: C, 63.95; H, 5.80; N,
2.98; S, 6.83. Found: C, 63.86; H, 5.83; N, 2.98; S, 6.79.
Method C: From 12a (300 mg, 0.77 mmol) in CH2Cl2
(5 ml), ZnBr2 (170 mg, 0.77 mmol) in CH2Cl2 (5 ml), and
diene 6 (1:1 cis±trans mixture, 0.42 ml, 3.8 mmol) at 258C
for 1 h, a mixture of adducts endo-32a and exo-32a (1:1,
330 mg, 89%) was obtained after chromatography (7:3 hex-
ane±AcOEt). Isomer endo-32a was isolated by crystalli-
zation from Et2O.
34%) were obtained after chromatography (1:1 hexane±
AcOEt).
With dihydropyridone 16a. Method C: From 16a (300 mg,
0.58 mmol) in CH2Cl2 (12 ml), ZnBr2 (130 mg, 0.58 mmol)
in CH2Cl2 (6 ml), and diene 6 (1:1 cis±trans mixture,
0.29 ml, 2.9 mmol) at 08C for 4 h, adduct exo-36a
(239 mg, 68%, accompanied by traces of three minor
diastereomers) was obtained after chromatography (4:1
hexane±AcOEt). An analytical sample of the major
diastereomer (4S,4aS,8S,8aR)-8a-(benzyloxycarbonyl)-4-
(tert-butyldimethylsilyloxy)-8-methoxy-1-oxo-2-(p-tolu-
enesulfonyl)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (exo-
36a) was obtained by chromatography (4:1 hexane±
AcOEt): 1H NMR (200 MHz) -0.04 and -0.03 (2s, 3H
each, Me2Si), 0.77 (s, 9H, t-Bu), 1.53 (ddm, Jˆ18.5,
11.5 Hz, 1H, 5-H), 2.09 (dtm, Jˆ19.2, 5.5 Hz, 1H, 5-H),
2.25 (s, 3H, MeTs), 2.73 (dt, Jˆ11.4, 6.2 Hz, 1H, 4a-H),
2.94 (s, 3H, OMe), 3.55 (dd, Jˆ13.3, 6.1 Hz, 1H, 3-H), 3.63
(dd, Jˆ13.2, 5.6 Hz, 1H, 3-H), 4.15 (d, Jˆ4.4 Hz, 1H, 8-H),
4.54 (q, Jˆ6 Hz, 1H, 4-H), 4.87 and 5.12 (2d, Jˆ12 Hz, 1H
each, CH2Ph), 5.61 (ddd, Jˆ10, 4.6, 2 Hz, 1H, 7-H), 5.71
(dm, Jˆ10 Hz, 1H, 6-H), 7.09±7.21 (m, 7H, PhH), 7.71 (d,
Jˆ8.4 Hz, 2H, Ts-o-H). Anal. Calcd for C31H41NO7SSi: C,
62.08; H, 6.89; N, 2.34; S, 5.34. Found: C, 61.71; H, 6.83;
N, 2.36; S, 5.11.
With dihydropyridone 12b. Method A: From 12b (500 mg,
1.73 mmol) and diene 6 (1:1 cis±trans mixture, 0.15 ml,
3.1 mmol) in p-cymene (8 ml) for 4 h, adducts 32b (3:2
mixture of endo and exo adducts, 75 mg, 12%) and endo-
32c (135 mg, 24%) were obtained after chromatography
(4:1 hexane±AcOEt). The assignment of 1H and 13C
NMR spectra of adducts 32b was performed by comparison
with spectra of other adducts of these series. (4aRS,8RS,
8aRS)-8a-(Benzyloxycarbonyl)-8-methoxy-2-(methoxy-
carbonyl)-1-oxo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline
1
(endo-32b): IR (KBr) 1770, 1727, 1640 cm21; H NMR
Diels±Alder reactions from (E)-1-(trimethylsilyloxy)-
buta-1,3-diene (7)
(200 MHz) 1.56 (dm, Jˆ13.6 Hz, 1H, 4-H), 1.96 (br s,
2H, 5-H), 2.45 (m, 1H, 4-H), 2.65 (dq, Jˆ13.6, 3.2 Hz,
1H, 4a-H), 3.17 (s, 3H, CO2Me), 3.08±3.23 (m, 1H, 3-
Hax), 3.61 (td, Jˆ11.6, 5.8 Hz, 1H, 3-Heq), 3.84 (s, 3H,
OMe), 4.45 (d, Jˆ4.4 Hz, 1H, 8-H), 5.10 and 5.30 (2d,
Jˆ12.2 Hz, 1H each, CH2Ph), 5.70±5.86 (m, 1H, 6-H),
6.01 (m, 1H, 7-H), 7.33 (m, 5H, PhH). Anal. Calcd for
C20H23NO6´1/4H2O: C, 63.57; H, 6.27; N, 3.71. Found: C,
63.6; H, 6.20; N, 3.56. (4aRS,8SR,8aRS)-Isomer (exo-
With dihydropyridone 12a. Method A: From 12a (500 mg,
1.29 mmol) and diene (E)-7 (0.78 ml, 4.5 mmol) in p-
cymene (10 ml) for 2 h, a residue was obtained after concen-
tration of the solvent. Anhydrous THF (50 ml) and CSA
(300 mg, 1.29 mmol) were added to the residue, and the
resulting solution was stirred at 08C for 1 h. After evapora-
tion of the solvent and addition of saturated aqueous
NaHCO3, the mixture was extracted with AcOEt. Concen-
tration of the dried organic extracts afforded a residue,
which was chromatographed (85:15 hexane±AcOEt) to
yield a mixture of adducts endo-33a and exo-33a (3:2,
190 mg, 28%) and dihydropyridone 10a (traces). Isomer
endo-33a was isolated by crystallization from Et2O.
(4aRS, 8RS, 8aRS)-8a-(Benzyloxycarbonyl)-1-oxo-2-(p-
toluenesulfonyl)-8-(trimethylsilyloxy)-1,2,3,4,4a,5,8,8a-
octahydroisoquinoline (endo-33a): mp 176±1788C (Et2O);
1
32b): IR (KBr) 1770, 1727, 1650 cm21; H NMR (200
MHz) 1.49±1.64 (m, 1H, 4-Heq), 1.78 (dd, Jˆ18.4,
12 Hz, 2H, 5-Hax), 2.26 (dt, Jˆ18.6, 5.4 Hz, 1H, 5-Heq),
2.34±2.56 (m, 1H, 4-Hax), 2.79±2.92 (m, 1H, 4a-H), 3.08±
3.24 (m, 1H, 3-Hax), 3.36 (s, 3H, CO2Me), 3.87 (s, 3H,
OMe), 4.12 (ddd, Jˆ14.4, 8, 4 Hz, 1H, 3-Heq), 4.35 (d,
Jˆ4 Hz, 1H, 8-H), 5.06 and 5.27 (2d, Jˆ12.4 Hz, 1H
each, CH2Ph), 5.7±5.86 (m, 1H, 6-H), 6.01 (m, 1H, 7-H),
7.35 (m, 5H, PhH). Anal. Calcd for C20H23NO6´1/4H2O: C,
63.57; H, 6.27; N, 3.71. Found: C, 63.6; H, 6.20; N, 3.56.
(4aRS,8RS,8aRS)-8a-(Benzyloxycarbonyl)-8-methoxy-1-
oxo-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (endo-32c):
;
IR (KBr) 1747, 1676, 1345, 1163 cm21 1H NMR
(200 MHz) 0.07 (s, 9H, Me3Si); 1.64 (m, 1H, 4-H), 1.97
(m, 2H, 5-H), 2.40 (s, 3H, MeTs), 2.62 (dm, Jˆ13.5 Hz,
1H, 4a-H), 2.73 (m, 1H, 4H), 3.85 (td, Jˆ11.5, 6 Hz, 1H,
3-Hax), 4.03 (ddd, Jˆ11.7, 5.2, 1.5 Hz, 1H, 3-Heq), 4.75 (d,
Jˆ4.3 Hz, 1H, 8-H), 5.09 and 4.96 (2d, Jˆ12.5 Hz, 1H
each, PhCH2), 5.67 (dt, Jˆ10.3, 3.8 Hz, 1H, 6-H), 5.78
(ddt, Jˆ10.2, 4.5, 2.2 Hz, 1H, 7-H), 7.13±7.34 (m, 7-H,
PhH and Ts-m-H), 7.93 (d, Jˆ8.3 Hz, 2H, Ts-o-H); MS,
m/z (rel intensity) 97 (45), 96 (39); 91 (51); 83 (60); 82
(41); 71 (51); 69 (75); 57 (100); 55 (81). Anal. Calcd for
C27H33O6NSSi: C, 61.45; H, 6.30; N, 2.65; S, 6.08. Found:
C, 61.55; H, 6.31; N, 2.60; S, 6.07. Spectroscopic data of the
(4aRS, 8SR,8aRS)-isomer (exo-33a) were inferred from an
endo/exo mixture: 1H NMR (200 MHz) 20.02 (s, 9H,
Me3Si); 1.20±3.20 (m, 5H, 4-H, 4a-H, 5-H), 2.44 (s, 3H,
MeTs), 3.95±4.15 (m, 1H, 3-Hax), 4.25 (m, 1H, 3-Heq),
1
IR (KBr) 3266, 1728, 1684, 1634 cm21; H NMR (300
MHz) 1.43 (dt, Jˆ13, 3.2 Hz, 1H, 4-Heq), 1.98 (m, 2H,
5-H), 2.44 (tdd, Jˆ13.5, 11.7, 6.7 Hz, 1H, 4-Hax), 2.68
(ddt, Jˆ13.7, 5, 3 Hz, 1H, 4a-H), 3.43 (m, 2H, 3-H), 3.41
(s, 3H, OMe), 4.38 (dd, Jˆ4.4, 0.8 Hz, 1H, 8-H), 5.12 and
5.27 (2d, Jˆ12 Hz, 1H each, CH2Ph), 5.74 (dt, Jˆ10.2,
4.2 Hz, 1H, 6-H), 6.03 (ddt, Jˆ10.3, 4.4, 2.4 Hz, 1H,
7-H), 6.50 (br s, 1H, NH), 7.33 (m, 5H, PhH). Anal. Calcd
for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.38;
H, 6.69; N, 4.35. Method C: From 12b (300 mg, 1.03 mmol)
in CH2Cl2 (5 ml), ZnBr2 (230 mg, 1.03 mmol) in CH2Cl2
(5 ml), and diene 6 (1:1 cis±trans mixture, 0.21 ml,
2 mmol) at 258C for 7 h, adducts endo-32b and exo-32b
(1:1 mixture, 125 mg, 32%) and aldehyde 34b (150 mg,

4042
N. Casamitjana et al. / Tetrahedron 56 (2000) 4027±4042
4.83 (d, Jˆ4.3 Hz, 1H, 8-H), 4.95 and 5.15 (2d, Jˆ12.5 Hz,
1H each, PhCH2), 5.65±5.85 (m, 2H, 6-H, 7-H), 7.10±7.40
(m, 7-H, PhH and Ts-m-H), 7.78 (d, Jˆ8.3 Hz, 2H, Ts-o-H).
Method C: From 12a (320 mg, 0.82 mmol) in CH2Cl2
(3 ml), ZnBr2 (164 mg, 0.73 mmol) in CH2Cl2 (2 ml), and
diene (E)-7 (0.7 ml, 4.2 mmol) at 258C for 30 min, adducts
endo-33a and exo-33a (1:1 mixture, 27 mg, 4%) and
aldehyde 34a (266 mg, 50%) were obtained after
chromatography (CH2Cl2±MeOH 1%). trans-3-(Benzyl-
oxycarbonyl)-4-[4-oxo-2(E)-butenyl]-1-(p-toluenesulfonyl)-
dimethylsilyloxy)-1-oxo-2-(p-toluenesulfonyl)-8-(trimethyl-
silyloxy)-1,2,3,4,4a,5,8,8a-octahydroisoquinoline (endo-
1
37a): IR (NaCl) 1741, 1720, 1361, 1172 cm21, H NMR
(300 MHz) 0.00 (s, 9H, Me3Si), 0.05 and 0.06 (2s, 3H
each, Me2Si), 0.89 (s, 9H, t-Bu), 1.60 (dd, Jˆ18.7,
11.5 Hz, 1H, 5-H), 2.15 (ddd, Jˆ18.7, 6.3, 3 Hz, 1H,
5-H), 2.36 (s, 3H, MeTs), 2.91 (dt, Jˆ11.9, 6.5 Hz, 1H,
4a-H), 3.44 (dd, Jˆ13.7, 5.9 Hz, 1H, 3-H), 3.76 (dd, Jˆ
13.7, 4.8 Hz, 1H, 3-H), 4.54 (q, Jˆ5.8 Hz, 1H, 4-H), 4.81
(m, 1H, 8-H), 5.02 and 5.15 (2d, Jˆ12.2 Hz, 1H each,
CH2Ph), 5.62 (br s, 2H, 6-H and 7-H), 7.20±7.32 (m, 7H,
PhH), 7.83 (d, Jˆ8 Hz, 2H, Ts-o-H). Anal. Calcd for
C33H47NO7SSi2: C, 60.24; H, 7.20; N, 2.13; S, 4.87.
Found: C, 60.24; H, 7.38; N, 2.10; S, 4.60.
1
2-piperidone (34a): H NMR (300 MHz) 1.63 (m, 1H,
5-H), 1.93±2.5 (m, 4H, 4-H, 10-H, 5-H), 2.39 (s, 3H,
MeTs), 3.18 (d, Jˆ10 Hz, 1H, 3-H), 3.61 (m, 1H, 6-H),
3.98 (m, 1H, 6-H), 5.43 (m, 2H, CH2Ph), 6.50 (m, 1H,
30-H), 6.81 (m, 1H, 20-H), 7.27 (d, Jˆ7.6 Hz, 2H, Ts-m-
H), 7.29 (m, 5H, PhH), 7.88 (d, Jˆ7.6 Hz, 2H, Ts-o-H),
9.47 (d, Jˆ7.7 Hz, 1H, CHO).
Acknowledgements
With dihydropyridone 12b. Method A: From 12b (500 mg,
1.73 mmol) and diene (E)-7 (1 ml, 5.7 mmol) in p-cymene
(8 ml) for 2.5 h, adducts endo-33b and exo-33b (1:1,
230 mg, 31%) were obtained after chromatography (7:3
hexane±AcOEt). (4aRS,8RS,8aRS)-8a-(Benzyloxycarbo-
nyl)-2-(methoxycarbonyl)-1-oxo-8-(trimethylsilyloxy)-1,2,
3,4,4a,5,8,8a-octahydroisoquinoline (endo-33b): IR (NaCl)
Financial support from DGICYT, Spain (project PB94-
0214) and the `Comissionat per a Universitats i Recerca',
Generalitat de Catalunya (Grant SGR99-00079) is grate-
fully acknowledged. Thanks are also due to the `Ministerio
Â
de Educacion y Cultura', Spain for a fellowship to V. L.
1
1777, 1739, 1725 cm21; H NMR (300 MHz) 0.08 (s, 9H,
Me3Si), 1.54 (m, 1H, 4-H), 1.95 (br s, 2H, 5-H), 2.66 (m, 2H,
4-H and 4a-H), 3.61 (m, 1H, 3-Hax), 3.86 (s, 3H, OMe),
3.75 (m, 1H, 3-Heq), 4.85 (d, Jˆ5 Hz, 1H, 8-H), 5.23 and
5.28 (2d, Jˆ12.4 Hz, 1H each, CH2Ph), 5.69 (m, 1H, 6-H),
5.79 (m, 1H, 7-H), 7.25 (s, 5H, PhH); MS, m/z (rel intensity)
416 (32), 297 (20), 296 (95) 280 (47), 264 (31), 142 (37), 91
(100), 65 (22). Anal. Calcd for C22H29NO6Si: C, 61.23; H,
6.77; N, 3.25. Found: C, 61.40; H, 6.88; N, 3.28. (4aRS,8SR,
References
1. (a) Indole and Biogenetically Related Alkaloids; Phillipson,
J. D., Zenk, M. H., Eds.; Academic Press: London, 1980. (b)
Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed. In The
Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.;
Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4.
2. For a preliminary report of a part of this work, see: Casamitjana,
Â
N.; Jorge, A.; Perez, C. G.; Bosch, J. Tetrahedron Lett. 1997, 38,
1
8aRS)-Isomer (exo-33b): IR (NaCl) 1752, 1725 cm21; H
NMR (300 MHz) 0.08 (s, 9H, Me3Si), 1.56 (dtd, Jˆ13, 6.5,
1 Hz, 1H, 4-H), 1.79 (dd, Jˆ18, 12 Hz, 1H, 5-Hax), 2.24 (dt,
Jˆ18, 6 Hz, 1H, 5-Heq), 2.34 (dtd, Jˆ14, 7.5, 4.5 Hz, 1H,
4-H), 2.92 (m, 1H, 4a-H), 3.03 (ddd, Jˆ14.5, 8, 7.5 Hz, 1H,
3-Hax), 3.82 (s, 3H, OMe), 4.06 (ddd, Jˆ14.5, 8, 4 Hz, 1H,
3-Heq), 5.00 (d, Jˆ4.4 Hz, 1H, 8-H), 5.08 and 5.29 (2d,
Jˆ12.4 Hz, 1H each, CH2Ph), 5.73 (m, 1H, 6-H), 5.81 (m,
1H, 7-H), 7.34 (s, 5H, PhH); MS, m/z (rel intensity) 297
(12); 296 (60); 280 (18); 264 (24); 192 (12); 91 (100).
Anal. Calcd for C22H29NO6Si: C, 61.23; H, 6.77; N, 3.25.
Found: C, 61.13; H, 6.75; N, 3.17. Method D: Operating as
in the above method D, from dihydropyridone 12b (289 mg,
1 mmol), diene (E)-7 (0.35 ml, 2 mmol) and EtAlCl2 (1 M
in hexane, 0.511.5 ml), aldehyde 34b (160 mg, 47%) was
obtained after chromatography (CH2Cl2±MeOH 5%).
2295±2298.
3. For related Diels±Alder reactions, see: (a) Imbroisi, D. O.;
Simpkins, N. S. J. Chem. Soc., Perkin Trans. I 1991, 1815±
Â
1823. (b) Gomez-Pardo, D.; d'Angelo, J. Tetrahedron Lett. 1992,
33, 6637±6640. (c) Torisawa, Y.; Nakagawa, M.; Takami, H.;
Nagata, T.; Ayman Ali, M.; Hino, T. Heterocycles 1994, 39,
277±292. (d) Torisawa, Y.; Hosaka, T.; Tanabe, K.; Suzuki, N.;
Motohashi, Y.; Hino, T.; Nakagawa, M. Tetrahedron 1996, 52,
10597±10608. See also references cited therein.
4. This compound was prepared as described in the literature: (a)
Herdeis, C. Synthesis 1986, 232±233. (b) Olsen, R. K.; Bhat, K. L.;
Wardle, R. B. J. Org. Chem. 1985, 50, 896±899.
5. Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in Organic
Synthesis; CRC Press: Boca Raton, 1996, pp 267±328.
6. Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96,
7807±7808.
With dihydropyridone 16a. Method C: From 16a (300 mg,
0.58 mmol) in CH2Cl2 (15 ml), ZnBr2 (130 mg, 0.58 mmol)
in CH2Cl2 (6 ml), and diene (E)-7 (0.5 ml, 2.9 mmol) at 08C
for 4 h, adduct endo-37a (14 mg, 4%) and aldehyde 38a
(48 mg, 14%, the major aldehyde obtained from diene 5)
were obtained after chromatography (4:1 hexane±AcOEt).
(4S,4aS,8R,8aR)-8a-(Benzyloxycarbonyl)-4-(tert-butyl-
7. For a related example, see: Avenoza, A.; Busto, J. H.; Cativiela,
C.; Peregrina, J. M. Tetrahedron 1994, 50, 12989±12998.
Â
8. Ouedraogo, A.; Tan Phan Viet, M.; Saunders, J. K.; Lessard, J.
Can. J. Chem. 1987, 65, 1761±1768.
9. Tanner, D.; Somfai, P. Tetrahedron 1988, 44, 613±618.
10. Herdeis, C.; Heller, E. Tetrahedron: Asymmetry 1993, 4,
2085±2094.