Diels-Alder reactions of 6-substituted 1-(p-nitrobenzoyl)-5,6-dihydro-2-pyridinones

Article abstract of DOI:10.1055/s-2002-19344

The first examples of Diels-Alder cycloaddition reactions of 6-substituted 1-(p-nitrobenzoyl)-5,6-dihydro-2-pyridinones are described. This reaction benefits from the fact that the diene adopts an endo orientation trans to the axial substituent at C-6 due to A^1,3 allylic type strain with the N-PNB protecting group.

Full text of DOI:10.1055/s-2002-19344

100
LETTER
Diels–Alder Reactions of 6-Substituted 1-(p-Nitrobenzoyl)-5,6-dihydro-2-
pyridinones
Diels–Alder
R
ea
u
ctions of 6-
S
ubstitu
z
ted1-(
p
-Nitroben
C
z
oyl)-5, 6-dihydr
.
o-2-pyridino
D
nes ias,*a Anna M. A. P. Fernandes,a J. Zukerman-Schpectorb
a
Instituto de Química, Universidade Estadual de Campinas/UNICAMP, C.P. 6154, CEP: 13083-970, Campinas, SP, Brazil
Fax +55(19)37883023; E-mail: ldias@iqm.unicamp.br
b
Departamento de Química/UFSCar, C.P. 676, CEP: 13565-905, São Carlos, SP, Brazil
Received 4 October 2001
This paper is dedicated to the Brazilian Chemical Society (SBQ)
first examples of Diels–Alder cycloaddition reactions of
6-substituted dihydropyridinones.
Abstract: The first examples of Diels–Alder cycloaddition reac-
tions of 6-substituted 1-(p-nitrobenzoyl)-5,6-dihydro-2-pyridino-
nes are described. This reaction benefits from the fact that the diene
adopts an endo orientation trans to the axial substituent at C-6 due
to A1,3 allylic type strain with the N-PNB protecting group.
Racemic dienophile 6a was prepared from commercially
available glutarimide 3 by the following sequence: methyl
magnesium bromide addition to glutarimide 3 followed
by treatment of the intermediate aminal with NaBH3CN/
HCl gave lactam 4 in 70% isolated yield (Scheme 1).6
N-protection of lactam 4 was achieved by using n-BuLi
in THF at –78 °C followed by addition of p-nitrobenzoyl
chloride to give imide 5 in 70% yield.
Key words: heterocycles, cycloadditions , -unsaturated lactams,
A1,3 allylic strain, cis-hydroisoquinoline
The cis-hydroisoquinoline moieties are present in a large
number of alkaloids belonging to different structural
types, most of them displaying notable pharmacological
activities.1–5 A variety of 5,6-dihydro-2-pyridinones have
been submitted to Diels–Alder conditions with a number
of different dienes and only in a few cases good results
were obtained.2,3 Recently, Casamitjana and coworkers
published a very interesting study involving a series of di-
hydropyridinones with a variety of dienes.4 In this work
the authors observed modest diastereofacial selectivities
when C-5-OTBS substituted dihydropyridinones were
used as dienophiles. Nakagawa and coworkers extensive-
ly studied this reaction in the synthesis of the tetracyclic
core of manzamine A.5
The electron-withdrawing group (PNB = p-nitrobenzoyl)
on the piperidine nitrogen is essential in order to enhance
the reactivity of the carbon-carbon double bond as a di-
enophile and also to place the methyl group at C-6 in axial
position due to A1,3 strain.7 Deprotonation of 5 with
LiHMDS in THF, followed by addition of phenylselenyl
bromide (1.5 equiv) gave the phenylselenide intermedi-
ate which could be cleanly converted to the dihydropyrid-
inone 6a in 50% yield over two-steps using standard
oxidation and elimination conditions (pyridine/H2O2).
1
Both H NMR (500 MHz) and single-crystal X-ray dif-
fraction analysis (Figure 1) showed that the methyl group
at C-6 occupies an axial position due to A1,3 strain with
the N-PNB protecting group (H6, 4.84 ppm, dt, J = 7.5
and 1.2 Hz, after selective irradiation of the methyl group
at 1.43 ppm).8
We wish to describe here our efforts towards the prepara-
tion of suitable functionalized cis-hydroisoquinolines
based on intermolecular Diels–Alder cycloaddition reac-
tions of 6-substituted-5,6-dihydro-2-pyridinones with
Danishefsky’s diene. We believe that developing a gener-
al and efficient Diels–Alder reaction using dihydropyrid-
inone derivatives bearing a chiral center at C-6 ( to the
nitrogen) would significantly enhance the utility of this
methodology. To the best of our knowledge, these are the
The thermally induced Diels–Alder reaction was best
conducted using the dihydropyridinone 6a and the highly
reactive Danishefsky’s diene 7 (5 equiv) in refluxing de-
gassed dry xylene in the presence of small amounts of 2,6-
di-tert-butyl-4-methylphenol
(BHT)
under
N2
(Scheme 2).9–11
1. CH3MgBr
n-BuLi (1 eq)
CH2Cl2/THF
p-nitrobenzoyl
-78°C to rt
1. LiHMDS (1 5 eq),
THF, -78°C
6
2
2
6
chloride
2
6
O
N
Me
O
N
Me
O
N
H
O
O
N
Me
2. NaBH3CN,
70%
-78°C, 70%
–O
2. PhSeBr
H
O
O
pH=3, rt,
3. H2O2, pyr., 0°C
(+/-)-4
–O
3
N+
O
N+
(+/-)-6a
(+/-)-5
50% (2 steps)
O
Scheme 1
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0100,0104,ftx,en;S06701st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Diels–Alder Reactions of 6-Substituted 1-(p-Nitrobenzoyl)-5,6-dihydro-2-pyridinones
101
Figure 1 ORTEP drawing of 6a
Figure 3 X-Ray structure of 8a
Treatment of the initially formed adduct with KF in THF/
H2O promoted the hydrolysis of the silyl enol ether func-
tionality and gave the endo-adduct 8a in 59% yield over
two-steps together with recovered starting material (6a,
10%).9–11
We next directed our attention to the synthesis of optically
active 2-hydroxymethyl-6-piperidinone 12 via an effi-
cient method starting from readily available and inexpen-
sive (S)-(+)-lysine monohydrochloride 9 (Scheme 3).12
Esterification and N-BOC protection of (S)-lysine gave
the protected derivative in very good overall yield (80%
over 2 steps). Oxidation with ruthenium oxide and sodium
periodate gave adipamide (S)-(+)-10 in 90% yield. Cy-
clization of (S)-(+)-10 to methyl 6-oxopipecolate (S)-(–)-
11 was achieved in refluxing trifluoroacetic acid (15 h,
70% yield). The next step involved sodium borohydride
reduction of (S)-(–)-11 to give the corresponding hy-
droxylactam in 80% yield.12 Subsequent protection of the
primary alcohol functionality as its p-methoxybenzyl
ether gave (S)-(+)-12 that after treatment with MeLi and
p-nitrobenzoyl chloride cleanly provided the N-PNB pro-
tected pyridinone (S)-(–)-13, a versatile intermediate, in
The illustrated NOESY interactions on the isoquinoline
nucleus, together with the large vicinal coupling constants
between H4ax-H10 (13.6 Hz), the small observed values be-
tween H3-H4eq (1.9 Hz), H3-H4ax (4.9 Hz), H9-H8 (3.0 Hz)
and the medium value for H9-H10 (8.3 Hz), unambiguous-
ly establish the proposed relative stereochemistry of the
Diels–Alder adduct 8a (Figure 2).
The structure of the cycloadduct 8a was subsequently
confirmed by a single-crystal X-ray structure determina-
tion, as shown in Figure 3.8
Me
O–
N+
6
OTMS
H
3
Me
O
O
2
O
N
O
6
10
1
1) xylene, reflux
BHT, 12h
+
N
1
8
O
2
OMe
H
2) KF, THF/H2O
59% (2 steps)
O
OMe
(+/-)-6a
7
(+/-)- 8a
N+
O
O–
Scheme 2
NOESY interactions
P = p-nitrobenzoyl
Coupling constants
P = p-nitrobenzoyl
H7
H8
H
O
6
O
MeO
H
J H4ax-H10 = 13.6 Hz
J H4eq-H10 = 4.1 Hz
H7
MeO
H
H4
J H8-H7ax = 3.1 Hz
J H8-H7eq = 2.9 Hz
5
H4
J H3-H4ax = 4.9 Hz
J H3-H4eq = 1.9 Hz
N
H9
H3
H
1
N
H
P
J H9-H10 = 8.3 Hz
J H9-H8 = 3.0 Hz
H
O
O
H10
P
Me
Me
Figure 2 NOESY interactions and coupling constants for 8a
Synlett 2002, No. 1, 100–104 ISSN 0936-5214 © Thieme Stuttgart · New York

102
L. C. Dias et al.
LETTER
65% yield (over 2 steps). Subsequent introduction of the expected product 8b in 60% isolated yield in two steps, to-
C3-C4 unsaturation to give (S)-(–)-6b was carried out via gether with recovered starting material (6b, 15%)
selenation (t-BuLi, DMPU, PhSeBr, –78 °C) and immedi- (Scheme 4).9–11
ate syn-elimination (pyridine/H2O2, CH2Cl2, r.t., 45%). A
better approach to (S)-(–)-6b involved protection of (S)-
(+)-12 as its acetonide followed by introduction of the
The relative stereochemistry of adduct 8b was proved by
analysis of the coupling constants in the H NMR spec-
trum (500 MHz) as well as by the illustrated NOESY in-
teractions on the isoquinoline nucleus (Figure 4). The
1
double bond (i.: LDA, THF, –78 °C; ii.: H2O2, pyridine,
CH2Cl2, r.t.) affording 14 in 48% overall yield (3 steps).12
large vicinal coupling constants between H4ax-H10 (13.6
Removal of the protecting group was achieved using the
Hz), the small observed values between H3-H4eq (1.9 Hz),
complex BF3 2 CH3CO2H in MeOH and protection of the
H3-H4ax (5.0 Hz), H9-H8 (2.7 Hz) and the medium value
primary alcohol as its PMB ether gave lactam 15 in 70%
for H9-H10 (6.8 Hz) unambiguously established the pro-
posed relative stereochemistry of Diels–Alder adduct 8b
(Figure 4).
overall yield for the two-step sequence.13 Treatment of 15
with MeLi and p-nitrobenzoyl chloride provided (S)-(–)-
1
6b in 70% yield. As expected, H NMR analysis (300
The stereochemical outcome of these Diels–Alder reac-
MHz) showed that the -CH2OPMB group at C-6 in both
tions involving N-PNB-6-substituted pyridinones is a re-
(S)-13 and (S)-6b occupies an axial position due to A1,3
sult of steric hindrance (allylic A1,3 strain) imposed by the
strain with the N-PNB protecting group [H6, 4.64 ppm, dd,
J = 3.8 and 5.8 Hz, after selective irradiation of the signals
at 3.72 and 3.65 ppm, corresponding to the methylenic hy-
drogens of the CH2OPMB group in (S)-13)].
adjacent substituent attached at C-6 and the nitrogen pro-
tecting group.7 These results are consistent with an endo
approach of the diene from the opposite side of this axial
substituent and are in contrast with the generally modest
diastereofacial selectivities observed by Casamitjana et al.
Heating of (S)-(–)-6b with an excess of Danishefsky’s di-
ene (10 equiv) at reflux in degassed dry xylene (20 h, un-
der N2) in the presence of catalytic amounts of 2,6-di-tert-
butyl-4-methylphenol (BHT), followed by treatment of
using C-5-OTBS substituted dihydropyridinones as di-
enophiles.4 These -substituted dihydropyridinones have
emerged as potential precursors for the construction of
the intermediate adduct with KF in aqueous THF gave the
1. (MeO)2CMe2,
HCl, MeOH
O
NHBoc
CO2Me
NH2.HCl 2. Boc2O, NaHCO3,
MeOH, sonicate
1. NaBH4,
EtOH
80%
TFA, ∆
(80%, 2 steps)
BocHN
H2N
CO2H
(S)-(+)-10
(S)-(+)-9
15h, 70%
3. RuO2, NaIO4, EtOAc
H2O, pH 4.5, 90%
O
N
CO2Me
H
2. PMB-
acetimidate
CH2Cl2, CSA
(S)-(-)-11
4
1. t-BuLi, DMPU
THF, –78 °C
2
6
OPMB
MeLi, ClPNB
THF, –78 °C, 65%
O
N
O
N
O
N
OPMB
2. PhSeBr, THF
–78 °C
(2 steps)
H
O
O
OPMB
(S)-(+)-12
–O
N+
3. H2O2, pyr
CH2Cl2, rt, 45%
–O
N+
O
(S)-(-)-6b
(S)-(-)-13
O
1. MeOPhCH(OMe)2
CSA, CH2Cl2, 79%
1. BF3-2AcOH
MeOH, rt
MeLi, ClPNB
THF, –78 °C, 70%
N
O
2. LDA, THF, –78 °C
PhSeBr
3. H2O2, pyr, rt
60% (2 steps)
2.PMB-acetimidate
CH2Cl2, CSA
O
N
O
H
OPMB
PMP
70% (2 steps)
(S)-(-)-15
(–)-14
Scheme 3
O–
N+
OPMB
6
PMBO
OTMS
H
6
O
3
O
N
2
O
+
10
1
1) xylene, reflux
BHT, 20h
N
8
1
O
2
OMe
H
2) KF, THF/H2O
60% (2 steps)
O
O
OMe
7
N+
(S)-(-)-6b
(-)- 8b
O
O–
Scheme 4
Synlett 2002, No. 1, 100–104 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diels–Alder Reactions of 6-Substituted 1-(p-Nitrobenzoyl)-5,6-dihydro-2-pyridinones
103
NOESY interactions
Coupling constants
P = p-nitrobenzoyl
P = p-nitrobenzoyl
H
H7
H8
O
O
6
H
MeO
J H4ax-H10 = 13.6 Hz
J H4eq-H10 = 4.3 Hz
H7
J H8-H7ax = 2.7 Hz
MeO
H4
H
J H8-H7eq = 1.5 Hz
H4
3
J H3-H4ax = 5.0 Hz
J H3-H4eq = 1.9 Hz
H
N
H
N
P
H9
H
O
P
J H9-H10 = 6.8 Hz
J H9-H8 = 2.7 Hz
O
H10
PMBO
PMBO
Figure 4 NOESY interactions and coupling constants for 8b
to carry out these reactions under the influence of various
Lewis acids, unsatisfactory results were obtained.
(10) (a) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289.
(b) Brocksom, T. J.; Nakamura, J.; Ferreira, M. L.;
Brocksom, U. J. Braz. Chem. Soc. 2001, 12, 597.
(11) It is interesting that we observed no loss of MeOH under
these conditions.
(12) (a) Hermitage, S. A.; Moloney, M. G. Tetrahedron:
Asymmetry 1994, 5(8), 1463. (b) Davies, C. E.; Heightman,
T. D.; Hermitage, S. A.; Moloney, M. G. Synth. Commun.
1996, 26, 687.
highly functionalized cis-hydroisoquinoline analogs with
potential relevance to biological studies.14
Acknowledgement
We are grateful to FAPESP for financial support and CNPq for fel-
lowships to both L.C.D. and A.M.A.P.F. We thank also Prof. Carol
H. Collins, from IQ-UNICAMP, for helpful suggestions about
English grammar and style, during the preparation of this manus-
cript.
(13) D’Aniello, F.; Taddei, M. J. Org. Chem. 1992, 57, 5247.
(14) 6-Methyl-2-piperidinone (+/–)-4: White powder; mp:
84.1–84.3 °C; IR (KBr): 3426, 3208, 2929, 1634, 797 cm–1;
1H NMR (500 MHz, CDCl3): = 1.16 (d, J = 6.3 Hz, 3 H,
CH3), 1.29 (m, 1 H, H-4), 1.65 (m, 1 H, H-4), 1.85 (m, 2 H,
H-5), 2.23 (ddd, J = 17.5, 10.7 and 6.1 Hz, 1 H, H-3), 2.33
(bd, J = 17.8 Hz, 1 H, H-3), 3.47 (m, 1 H, H-6), 6.92 (bs, 1
H, NH); 13C NMR (125 MHz, CDCl3): = 19.6 (C-4), 22.5
(CH3), 30.3 (C-5), 30.8 (C-3), 48.5 (C-6), 172.5 (C-2); MS:
m/z (rel. intensity) = 113(25) [M+], 98(100), 85(4), 70(8),
55(51), 42(31); TLC: Rf = 0.42 (EtOAc–MeOH, 90:10).
6-Methyl-1-(4-nitrobenzoyl)-2-piperidinone (+/–)-5:
Yellow oil; IR (KBr): 3112, 3076, 2957, 1709, 1681, 1520,
1259, 1163 cm–1; 1H NMR (500 MHz, CDCl3): = 1.38 (d,
J = 6.6 Hz, 3 H, CH3), 1.89 (m, 2 H, H-4), 2.10 (m, 2 H, H-
5), 2.55 (m, 2 H, H-3), 4.60 (m, 1 H, H-6), 7.60 (dt, J = 2.0
and 8.8 Hz, 2 H, NO2-m-H), 8.21 (dt, J = 2.0 and 8.8 Hz,
NO2-o-H); 13C NMR (125 MHz, CDCl3): = 17.3 (C-4),
19.8 (CH3), 28.9 (C-5), 34.1 (C-3), 51.5 (C-6), 123.4 (C-m-
NO2), 127.9 (C-o-NO2), 142.9 (C-p-NO2), 148.7 (C-i-NO2),
172.2 (C-2, CO), 174.1 (COPhNO2); MS: m/z (rel. intensity)
= 262(9) [M+], 245(8), 219(13), 150(100), 112(52), 104(34),
76(25); Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N,
10.68. Found: C, 59.47; H, 5.46; N, 10.71; HRMS calcd
262.0953, found 262.0952; TLC: Rf = 0.49 (Et2O–hexanes,
90:10).
References
(1) (a) Ornstein, P. L.; Augenstein, N. K.; Arnold, M. B. J. Org.
Chem. 1994, 59, 7862. (b) Ornstein, P. L.; Arnold, M. B.;
Allen, N. K.; Bleish, T.; Borromeo, P. S.; Lugar, C. W.;
Leander, J. D.; Lodge, D.; Schoepp, D. D. J. Med. Chem.
1996, 39, 2232.
(2) (a) Imbroisi, D. O.; Simpkins, N. S. Tetrahedron Lett. 1989,
30, 4309. (b) Nakagawa, M.; Lai, Z.; Torisawa, Y.; Hino, T.
Heterocycles 1990, 31, 999. (c) Imbroisi, D. O.; Simpkins,
N. S. J. Chem. Soc., Perkin Trans 1 1991, 1815.
(d) Torisawa, Y.; Nakagawa, M.; Hosaka, T.; Tanabe, K.;
Lai, Z.; Ogata, K.; Nakata, T.; Oishi, T.; Hino, T. J. Org.
Chem. 1992, 57, 5741.
(3) (a) Torisawa, Y.; Nakagawa, M.; Takami, H.; Nagata, T.;
Ali, M. A.; Hino, T. Heterocycles 1994, 39, 277.
(b) Torisawa, Y.; Ali, M. A.; Tavet, F.; Kageyama, K.;
Aikawa, M.; Fukui, N.; Hino, T.; Nakagawa, M.
Heterocycles 1996, 42, 677. (c) Torisawa, Y.; Hosaka, T.;
Tanabe, K.; Suzuki, N.; Motohashi, Y.; Hino, T.; Nakagawa,
M. Tetrahedron 1996, 32, 10597.
(4) Casamitjana, N.; López, V.; Jorge, A.; Bosch, J.; Molins, E.;
Roig, A. Tetrahedron 2000, 56, 4027.
(5) (a) Uchida, H.; Nishida, A.; Nakagawa, M. Tetrahedron
Lett. 1999, 40, 113. (b) Nakagawa, M.; Torisawa, Y.;
Ushida, H.; Nishida, A. J. Synth. Org. Chem. Jpn. 1999, 57,
1004. (c) Nakagawa, M. J. Heterocycl. Chem. 2000, 37, 567.
(6) Maldaner, A. O.; Pilli, R. A. Tetrahedron 1999, 55, 13321.
(7) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.
(8) A complete crystal structure description of 6a and 8a is
being published elsewhere: Zukerman-Schpector, J.; Vega,
M.; Caracelli, I.; Dias, L. C.; Fernandes, A. M. A. P. Acta
Cryst. 2001, C57, 1089.
(9) Initial attempts at Diels–Alder reactions with a N-tert-
butoxycarbonyl (BOC) derivative and the highly reactive
Danishefsky’s diene failed to afford the expected adducts
under either thermal or Lewis acid conditions. Under both
conditions we observed loss of the BOC group. In an attempt
6-Methyl-1-(4-nitrobenzoyl)-5,6-dihydro-2-pyridinone
(+/–)-6a: Yellow powder; mp: 113.7–114.6 °C; IR (KBr):
3118, 2975, 1690, 1681, 1604, 1532, 1303, 850 cm–1; 1H
NMR (300 MHz, CDCl3): = 1.43 (d, J = 6.6 Hz, 3 H, CH3),
2.41 (ddt, J = 0.7, 6.2 and 18.7 Hz, 1 H, H-5), 2.94 (ddt,
J = 2.7, 6.3 and 18.6 Hz, 1 H, H-5), 4.84 (qt, J = 7.5 Hz, 1 H,
H-6), 5.99 (ddd, J = 0.7, 2.6 and 9.9 Hz, 1 H, H-3), 6.92 (m,
1 H, H-4), 7.62 (dt, J = 2.1 and 8.9 Hz, 2 H, NO2-m-H), 8.24
(dt, J = 2.9 and 9.0 Hz, 2 H, NO2-o-H); 13C NMR (75 MHz,
CDCl3): = 18.9 (CH3), 31.0 (C-5), 49.6 (C-6), 123.3 (C-m-
NO2), 124.3 (C-3), 128.3 (C-o-NO2), 142.5 (C-p-NO2),
144.2 (C-4), 148.8 (C-i-NO2), 164.6 (C-2), 171.4
(COPhNO2); MS: m/z (rel. intensity) = 260(11) [M+],
Synlett 2002, No. 1, 100–104 ISSN 0936-5214 © Thieme Stuttgart · New York

104
L. C. Dias et al.
LETTER
243(6), 232(11), 217(15), 150(100), 110(44), 68(55);
HRMS calcd 260.0797, found 260.0796; TLC: Rf = 0.29
(hexanes–EtOAc, 50:50).
(75 MHz, CDCl3): = 18.2 (C-4), 25.2 (C-5), 34.1 (C-3),
54.3 (C-6), 55.1 (OCH3), 70.1 (CH2O), 73.0 (CH2Ph), 113.8
(C-m-OCH3), 123.5 (C-m-NO2), 128.3 (C-o-NO2), 129.3 (C-
o-OCH3), 129.7 (C-p-OCH3) 142.4 (C-p-NO2), 149.0 (C-i-
NO2), 159.4 (C-i-OCH3), 172.6 (C-2), 174.4 (COPhNO2);
MS: m/z (rel. intensity) = 398(3) [M+], 248(12), 150(60),
121(100), 98(50), 78(10), 55(14); HRMS calcd 398.1477,
found 398.1474; TLC: Rf = 0.35 (hexanes–EtOAc, 65:35).
(8aS,3R)-3-(4-Methoxyphenyl)-1,5,8,8a-tetrahy-
dro[1,3]oxazolo[3,4-a]pyridin-5-one (–)-14: Light brown
oil; [ ]D25 –113 (c 1.0, CHCl3); IR (KBr): 2928, 1656, 1519,
1448 cm–1; 1H NMR (500 MHz, CDCl3): = 2.34 (m, 1 H),
2.55 (dt, J = 6.1 and 17.3, 1 H), 3.77 (t, J = 8.2 Hz, 1 H), 3.80
(s, 3 H), 4.20 (m, 1 H), 4.43 (dd, J = 6.3 and 8.3 Hz, 1 H),
5.96 (dd, J = 2.9 and 10.0 Hz, 1 H), 6.32 (s, 1 H), 6.53 (ddd,
J = 2.5, 6.7 and 9.4 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 7.40
(d, J = 8.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3): = 27.3,
53.8, 55.2, 72.8, 88.7, 113.7, 125.8, 127.8, 130.7, 137.0,
159.7, 160.5; MS: m/z (rel. intensity) = 245(70) [M+],
214(6), 176(8), 135(100), 122(17), 96(50), 77(10); HRMS
calcd 245.1051, found 245.1055; TLC: Rf = 0.33 (hexanes–
EtOAc, 20:80).
(–)-(6S)-(4-Methoxybenzyloxymethyl)-2-oxo-1,2,3,6-
tetrahydro-1-pyridinyl-4-nitrophenylmethanone
(S)-(–)-6b: Light brown oil; IR (KBr): 3065, 2935, 2861,
1691, 1609, 1520, 1348, 1290, 1233, 1176, 1110 cm–1; 1H
NMR (300 MHz, CDCl3): = 2.81 (m, 2 H, H-5), 3.61 (t,
J = 8.8 Hz, 1 H, CH2O), 3.70 (dd, J = 4.7 and 9.5 Hz, 1 H,
CH2O), 3.82 (s, 3 H, OCH3), 4.46 (d, J = 11.4 Hz, 1 H,
CH2Ph), 4.52 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.89 (m, 1 H, H-
6), 5.95 (dt, J = 2.0 and 9.9 Hz, 1 H, H-3), 6.83 (m, 1 H, H-
4), 6.89 (dt, J = 2.3 and 8.4 Hz, 2 H, OCH3-m-H), 7.24 (dt,
J = 2.2 and 8.4 Hz, 2 H, OCH3-o-H) 7.61 (dt, J = 2.2 and 8.8
Hz, 2 H, NO2-m-H), 8.24 (dt, J = 2.2 and 9.1 Hz, 2 H, NO2-
o-H); 13C NMR (75 MHz, CDCl3): = 26.1 (C-5), 52.2 (C-
6), 55.2 (OCH3), 68.4 (OCH2), 73.0 (CH2Ph), 113.8 (C-m-
OCH3), 123.4 (C-m-NO2), 124.3 (C-3), 128.4 (C-o-NO2),
129.3 (C-o-OCH3), 129.7 (C-p-OCH3) 142.2 (C-p-NO2),
144.0 (C-4), 148.9 (C-i-NO2), 159.4 (C-i-OCH3), 164.4 (C-
2), 171.4 (COPhNO2); MS: m/z (rel. intensity) = 396(2)
[M+], 245(6), 150(41), 121(100), 104(27), 78(23); HRMS
calcd 396.1321, found 396.1358; TLC: Rf = 0.38 (hexanes–
EtOAc, 60:40).
8-Methoxy-3-(4-methoxybenzyloxymethyl)-2-(4-nitro-
benzoyl)perhydro-1,6-isoquinolinedione (–)-8b: Light
brown oil; IR (KBr): 3110, 2960, 1711, 1680, 1521, 1350,
1300, 1230, 1110 cm–1; 1H NMR (500 MHz): = 2.02 (ddd,
J = 1.9, 4.3 and 13.6 Hz, 1 H, H-4eq), 2.28 (dt, J = 5.0 and
13.6 Hz, 1 H, H-4ax), 2.36 (dd, J = 2.7 and 16.5 Hz, 1 H, H-
7ax), 2.47 (dd, J = 6.1 and 15.0 Hz, 1 H, H-5), 2.61 (dd,
J = 7.4 and 15.0 Hz, 1 H, H-5), 2.81 (dd, J = 2.7 and 6.9 Hz,
1 H, H-9), 2.86 (dd, J = 1.5 and 16.5 Hz, 1 H, H-7eq), 3.05
(m, 1 H, H-10), 3.38 (s, 3 H, OCH3 in C-8), 3.72 (dd, J = 2.7
and 9.7 Hz, 1 H, CH2O), 3.80 (m, 4 H, OCH3 and CH2O),
4.29 (m, 1 H, H-8), 4.41 (d, J = 11.6 Hz, 1 H, CH2Ph) 4.46
(d, J = 11.6 Hz, 1 H, CH2Ph), 4.60 (m, 1 H, H-3), 6.86 (d,
J = 8.5 Hz, 2 H, OCH3-m-H), 7.17 (d, J = 8.5 Hz, OCH3-o-
H), 7.71 (d, J = 8.8 Hz, 2 H, NO2-m-H), 8.23 (d, J = 8.8 Hz,
2 H, NO2-o-H); 13C NMR (75 MHz, CDCl3): = 29.7 (C-
10), 32.9 (C-4), 41.7 (C-5), 44.4 (C-7), 46.8 (C-9), 53.9 (C-
3), 55.3 (CH3OPh) 56.7 (OCH3), 70.6 (OCH2), 73.3
(CH2Ph), 81.1 (C-8), 113.9 (C-m-OCH3), 123.4 (C-m-NO2),
128.4 (C-o-NO2), 129.4 (C-o-OCH3) 129.5 (C-p-OCH3),
142.2 (C-p-NO2), 149.0 (C-i-NO2), 159.4 (C-i-OCH3), 172.4
(C-1), 174.3 (COPhNO2), 208.1 (C-6, CO); HRMS calcd
496.1845, found 496.1841; TLC: Rf = 0.28 (hexanes–
EtOAc, 50:50).
8-Methoxy-3-methyl-2-(4-nitrobenzoyl)perhydro-1,6-
isoquinolinedione (+/–)-8a: General procedure: A mixture
of the dienophile (6a) (50 mg, 0.19 mmol), 2,6-di-tert-butyl-
4-methylphenol (42 mg, 0.19 mmol) and Danishefsky’s
diene (0.40 mL, 10 equiv) in degassed dry xylene (3 mL)
was refluxed for 20 h under Ar. After being cooled to r.t., the
mixture was concentrated under reduced pressure to afford a
crude residue, which was taken into THF (3 mL) and H2O (1
mL) and treated with KF (40 mg) at r.t. for 2 h. The mixture
was diluted with CH2Cl2 (100 mL) and extracted. The
combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated to give, after
chromatography (flash, SiO2, 100% Et2O) 8a as a pale
yellow powder: Mp: 188.6–189.4 °C; IR (KBr): 3118, 3071,
2963, 1716, 1693, 1670, 1608, 1528, 1344, 1264 and 858
cm–1; 1H NMR (500 MHz, CDCl3): = 1.46 (d, J = 6.6 Hz,
3 H, CH3), 1.77 (ddd, J = 1.9, 4.1 and 13.6 Hz, 1 H, H-4),
2.40 (dt, J = 4.9 and 13.6 Hz, 1 H, H-4), 2.44 (dd, J = 3.2 and
16.1 Hz, 1 H, H-7), 2.52 (dd, J = 5.2 and 15.5 Hz, 1 H, H-5),
2.70 (dd, J = 7.6 and 15.5 Hz, 1 H, H-5), 2.89 (dd, J = 3.0
and 8.3 Hz, 1 H, H-9), 2.92 (bd, J = 16.1 Hz, 1 H, H-7), 2.97
(m, 1 H, H-10), 3.40 (s, 3 H, OCH3), 4.33 (dd, J = 3.0 and 5.9
Hz, 1 H, H-8), 4.60 (qdd, J = 1.9, 6.6 and 4.9, 1 H, H-3), 7.69
(dt, J = 2.1 and 9.1 Hz, 2 H, NO2-m-H), 8.24 (dt, J = 2.1 and
9.2 Hz, 2 H, NO2-o-H); 13C NMR (125 MHz, CDCl3):
=
20.3 (CH3), 28.4 (C-10), 34.7 (C-4), 41.8 (C-5), 44.1 (C-7),
46.4 (C-9), 50.9 (C-3), 56.8 (OCH3), 81.2 (C-8), 123.4 (C-m-
NO2), 128.1 (C-o-NO2), 142.5 (C-p-NO2), 148.8 (C-i-NO2),
172.2 (C-1, CO), 173.7 (COPhNO2), 207.6 (C-6, CO); MS:
m/z (rel. intensity) = 360(10) [M+], 210(82), 178(12),
150(100), 120(12), 57(40); Anal. Calcd for C18H20N2O6: C,
59.99; H, 5.59; N, 7.77. Found: C, 59.93; H, 5.66; N, 7.64;
HRMS calcd 360.1321, found 360.1324; TLC: Rf = 0.20
(Et2O).
(–)-(6S)-(4-Methoxybenzyloxymethyl)-2-piperidinone
(S)-(+)-12: Colorless oil; [ ]D25 +14.6 (c 1.75, CHCl3); IR
(KBr): 3397, 2944, 1658, 1514, 1462, 1247, 1092, 1032 cm–
1; 1H NMR (300 MHz, CDCl3): = 1.26 (m, 1 H, H-5), 1.68
(m, 1 H, H-4), 1.84 (m, 2 H, H-5), 2.26 (ddd, J = 17.5, 11.0
and 6.2 Hz, 1 H, H-3), 2.40 (brd, J = 17.5 Hz, 1 H, H-3), 3.23
(t, J = 9.1 Hz, 1 H, CH2O), 3.47 (dd, J = 3.6 and 9.2 Hz, 1 H,
CH2O), 3.60 (ddd, J = 4.0, 9.6 and 13.6 Hz, 1 H, H-6), 3.80
(s, 3 H, OCH3), 4.41 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.46 (d,
J = 11.4 Hz, 1 H, CH2Ph), 6.24 (brs, 1 H, NH), 6.89 (dt,
J = 2.5 and 8.8 Hz, 2 H, OCH3-m-H), 7.23 (dt, J = 2.2 and
8.8 Hz, 2 H, OCH3-o-H); 13C NMR (75 MHz, CDCl3):
=
19.5 (C-5), 24.6 (C-4), 31.4 (C-3), 52.5 (C-6), 55.2 (OCH3),
72.9 (CH2O), 73.4 (CH2Ph), 113.8 (C-m-OCH3), 129.3 (C-o-
OCH3), 129.5 (C-p-OCH3), 159.3 (C-i-OCH3), 171.8 (C-2);
MS: m/z (rel. intensity) = 249(3) [M+], 121(41), 113(48),
98(100), 78(9), 69(28), 55(35); HRMS calcd 249.1364,
found 249.1362; TLC: Rf = 0.30 (hexanes–EtOAc, 10:90).
(–)-(6S)-(4-Methoxybenzyloxymethyl)-1-(4-nitro-
benzoyl)-2-piperidinone (S)-(–)-13: Yellow oil; [ ]D
25
–
11.4 (c 2.24, CHCl3); IR (KBr): 3112, 3071, 2959, 1710,
1676, 1613, 1522, 1350, 1300, 1253 cm–1; 1H NMR (300
MHz, CDCl3): = 1.86 (m, 1 H, H-5), 2.00–2.20 (m, 3 H, H-
4 and H-5), 2.53 (m, 2 H, H-3), 3.65 (dd, J = 3.5 and 9.7 Hz,
1 H, CH2O), 3.72 (dd, J = 6.0 and 9.3 Hz, 1 H, CH2O), 3.80
(s, 3 H, OCH3), 4.40 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.44 (d,
J = 11.4 Hz, 1 H, CH2Ph) 4.64 (m, 1 H, H-6), 6.85 (dt,
J = 2.4 and 9.2 Hz, 2 H, OCH3-o-H), 7.17 (dt, J = 2.4 and 9.3
Hz, 2 H, OCH3-m-H) 7.61 (dt, J = 2.1 and 8.9 Hz, 2 H, NO2-
m-H), 8.20 (dt, J = 2.2 and 9.1 Hz, 2 H, NO2-o-H); 13C NMR
Synlett 2002, No. 1, 100–104 ISSN 0936-5214 © Thieme Stuttgart · New York