Highly diastereoselective intramolecular α-amidoalkylation reactions of hydroxylactams derived from N-phenethylimides. Enantioselective synthesis of dihydropyrrolo[2,1-a] isoquinolones

Article abstract of DOI:10.1055/s-2002-22703

α-Hydroxylactams, derived from organolithium addition to an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-dicarboxyimide with a 2-exo-hydroxy-10-bornylsulfinyl group as chiral auxiliary, undergo efficient and highly diastereoselective N-acylimini

Full text of DOI:10.1055/s-2002-22703

LETTER
593
Highly Diastereoselective Intramolecular -Amidoalkylation Reactions of
Hydroxylactams Derived from N-Phenethylimides. Enantioselective Synthesis
of Dihydropyrrolo[2,1-a] isoquinolones
D
iastereo
n
selective -A
é
midoalkyl
s
ation Reactions
G
of
H
ydroxylactam
o
s
nzález-Temprano, Nuria Sotomayor, Esther Lete*
Departamento de Química Orgánica II, Facultad de Ciencias, Universidad del País Vasco, Apdo. 644-48080 Bilbao, Spain
Fax +34(94)4648500; E-mail: qopleexe@lg.ehu.es
Received 29 January 2002
intramolecular conjugate additions, has been accom-
Abstract: -Hydroxylactams, derived from organolithium addition
plished.
to an enantiomerically pure N-phenethylnorborn-5-en-endo-2,3-di-
carboxyimide with a 2-exo-hydroxy-10-bornylsulfinyl group as
chiral auxiliary, undergo efficient and highly diastereoselective N-
acyliminium ion cyclization. Subsequent removal of the auxiliary
and retro-Diels-Alder reaction lead to the enantioselective synthesis
of C-10b substituted 5,6-dihydropyrrolo[2,1-a]isoquinolines.
In this context, our next challenge was to achieve the
asymmetric synthesis of these nitrogen heterocycles.
Thus, we reasoned that if a chiral auxiliary is appended to
the norbornene moiety, enantiomerically pure isoindolo-
isoquinolines 2 could be obtained. Removal of the chiral
auxiliary, followed by retro Diels-Alder reaction would
afford enantiopure C-10b substituted dihydropyrroliso-
quinolines 1. This methodology would open up an asym-
metric route to erythrinan alkaloids avoiding the release of
the carboxyl group required in the above-described proto-
cols.7 For this purpose, we chose the 2-exo-hydroxy-10-
bornylsulfinyl group as chiral auxiliary.9 Thus, our imide
precursor would be (2-exo-hydroxy-10-bornyl)sulfinyl-
norbornenimide 3 (Scheme 1).
Key words: asymmetric synthesis, chiral auxiliaries, organolithi-
um addition, cyclization, N-acyliminium ion
The pyrrolo[2,1-a]isoquinolines represent a structural
fragment of erythrinan alkaloids with significant pharma-
cological activity. These compounds possess antidepres-
sant,1 muscarinic agonist,2 and antileukemic3 properties.
Moreover, they can be used as PET radiotracers for imag-
ing serotonin uptake sites.4 The importance of the pyrro-
lo[2,1-a]isoquinolines 1 is further enhanced by their
utility as advanced intermediates for the synthesis of
erythrinan alkaloids.5 Thus, introduction of a C-4 unit into
a dihydropyrroloisqouinoline by the Diels-Alder reaction
or a [2+2] photocycloaddition is among the most impor-
tant procedures for building up the erythrinan ring sys-
tem.6 These methods have also been applied to the total
synthesis of enantiomerically pure aromatic erythrinan al-
kaloids, using L-DOPA as precursor of a chiral pyrrolo-
isoquinolone.7 However, both strategies require several
steps for the removal of the carboxyl group of the starting
amino acid in the final stages of the synthesis.
CH3O
CH3O
CH3O
CH3O
N
N
O
O
R3
R3
H
R1
S
O
1
2
CH3O
N
O
S
CH3O
O
R1
O
R1
=
OH
H
On the other hand, we have reported that N-phenethylnor-
born-5-en-endo-2,3-dicarboxyimide could be considered
as a synthetic equivalent of N-phenethylmaleimide in the
organolithium addition-N-acyliminium ion cyclization se-
quence, as it carries a masked , -unsaturated imide moi-
ety, that could be released by a retro-Diels-Alder
reaction.8 This methodology has been extended to the use
of functionalized organolithium reagents capable of 1,2-
addition to the carbonyl group, such as 3-(2-trimethylsi-
lyl-1,3-dithian-2-yl)propyllithium. Thus, the synthesis of
C-10b functionalized dihydropyrrolo[2,1-a]isoquino-
lines, immediate precursors for erythrinan alkaloids via
3
Scheme 1 Retrosynthetic analysis.
Preparation of imide 3 was carried out using the procedure
developed by Arai9a,b for related substrates, which relies
on an asymmetric Diels-Alder reaction of a sulfinylmale-
imide.10–12 Thus, our first task was the synthesis of N-
phenethylmaleimide 7. As depicted in Scheme 2, addition
of 10-mercaptoisoborneol to maleimide 4 afforded suc-
cinimide 5 as a 95:5 diastereoisomeric mixture in good
yield. Treatment with NCS afforded maleimide 6, which
was oxidized with MCPBA to yield sulfinylmaleimide 7
as a single diastereoisomer in excellent yield.13
Diels-Alder reaction of sulfinylmaleimide 7 with cyclo-
pentadiene in the presence of ZnCl2 afforded sulfinylnor-
bornenimide 3 in excellent yield (93%), as a single
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0593,0597,ftx,en;D01902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

594
I. González-Temprano et al.
LETTER
CH3O
CH3O
CH3O
a
Cl
R1
b
N
O
R1
O
Cl
N
O
O
O
O
S
CH3O
O
S
O
endo
2
N
R
R1S
N R2
4
5 (dr 95:5, 86%)
O
O
CH3O
CH3O
CH3O
3
c
N
O
N
O
O
CH3O
O
ZnCl2
O
R1S
S
R1
R1
O
O
S
S
6 (84%)
7 (97%)
O
O
endo
R1
N R2
Scheme 2 (a) Mercaptoisoborneol, Et3N, 0 °C to r.t., 24 h; (b) NCS,
R2
N
CCl4, reflux, 16 h; (c) MCPBA, CH2Cl2, 0 °C, 3 h.
O
O
8
Figure 1 Diels-Alder reaction of 7.
diastereoisomer (Scheme 3). The stereochemical outcome
of the reaction may be explained as shown in Figure 1. In
the presence of ZnCl2, formation of a zinc chelate with
sulfinyl and carbonyl oxygen atoms would direct the at-
tack of cyclopentadiene from the less hindered side to af-
ford the endo product 3. In the absence of ZnCl2, a more
stable conformer due to dipole-dipole repulsion would
lead to the formation of endo product 8. In fact, when the
cycloaddition reaction was carried out in the absence of a
Lewis acid, a diastereoisomeric mixture of 3 and 8 was
obtained in a 33:67 ratio (90%).
the isoquinoline nucleus by an intramolecular -ami-
doalkylation reaction. As depicted in Scheme 3, treatment
of -hydroxylactams 9a,b with an excess of TFA at room
temperature furnished the expected isoquinoline 2a,b, to-
gether with their derivatives 10a,b, in which trifluoro-
acetylation of the hydroxyl group of the auxiliary had
occurred. These products were separated and character-
ized independently, but as will be discussed later, this side
reaction had no relevance in the following steps. Thus,
considering the combined yield of both isoquinolines 2
and 10, the intramolecular -amidoalkylation reaction ef-
ficiently afforded the isoquinoline system with complete
stereocontrol, as isoindoloisoquinolines 2 and 10 were
isolated as single diastereoisomers. The observed stere-
ochemistry is consistent with the aromatic ring approach-
ing the intermediate N-acyliminium ion from the less
hindered Si side, which resulted in an R configuration for
the newly created C-12b stereogenic centre. In this case,
the C10-C11 ethylydene bridge of the endo-norbornene
moiety would block the Re side.14
CH3O
N
O
S
a
CH3O
O
7
R1
H
O
3 (93%)
CH3O
b
N
O
S
+
3
7
CH3O
O
R1
H
O
dr 3:8 = 33:67 (90%)
The chiral auxiliary was reductively removed by treat-
ment with an excess of SmI2 in the presence of HMPA and
t-BuOH.14 Thus, 2a,b and their O-trifluoroacetyl deriva-
tives 10a,b were converted separately into the same iso-
indoloisoquinolines 11a,b in high yields and excellent
(>99%) enantiomeric excesses (Scheme 5, Table).15 Spec-
troscopic data of 11a and 11b were in agreement with
those of the corresponding racemates previously reported
by us,8b which confirms, on one hand, the endo stereo-
chemistry of the norbornene moiety, and on the other, the
relative stereochemistry of the methyl or butyl groups.
8
Scheme 3 (a) Cyclopentadiene, ZnCl2, CH2Cl2, 0 °C; (b) Cyclopen-
tadiene, CH2Cl2, 0 °C.
Once the chiral non-racemic imide precursor 3 had been
prepared, we studied the stereoselectivity of the organo-
lithium addition-N-acyliminium ion cyclization sequence.
Thus, addition of MeLi or BuLi (2.3 equiv) to imide 3 af-
forded -hydroxylactams 9 in quantitative yields as single
diastereoisomers (Scheme 4). As expected, attack of the
organolithium took place regioselectively at the less hin-
dered carbonyl group. It was not necessary to determine
the stereochemistry of -hydroxylactams 9, as a planar N-
acyliminium ion was going to be generated in the subse-
quent cyclization. The next step was the construction of
Finally, retro-Diels-Alder reaction17 of 11a,b using an
FVP technique produced the , -unsaturated pyrroloiso-
quinolines 1a,b in high yield and enantiomeric purity,
without racemization.16
Synlett 2002, No. 4, 593–597 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective -Amidoalkylation Reactions of Hydroxylactams
595
CH3O
CH3O
lactams. In fact, organolithium addition-N-acyliminium
ion cyclization sequence on an enantiomerically pure N-
phenethylnorborn-5-en-endo-2,3-dicarboxyimide, with a
2-exo-hydroxy-10-bornylsulfinyl group as chiral auxilia-
ry, proceeds with high stereocontrol.
a
b
N
O
S
3
HO
R3
R1
H
O
9a R3 = CH3 (99%)
9b R3 = Bu (99%)
Acknowledgement
Financial support from Gobierno Vasco (PI-1999-165), MCYT
(BQU2000-0223), and Universidad del País Vasco is gratefully
acknowledged. We also thank the UPV for a grant (I.G.-T.).
CH3O
CH3O
CH3O
N
N
O
O
CH3O
R1
R3
H
R3
H
R4
S
S
References
O
O
(1) (a) Elwan, N. M.; Abelhadi, H. A.; Abdallah, T. A.;
Hassaneen, H. M. Tetrahedron 1996, 52, 3451.
2a R3 = CH3 (51%)
2b R3 = Bu (23%)
10a R3 = CH3 (16%)
10b R3 = Bu (63%)
(b) McComsey, D. F.; Maryanoff, B. E. J. Org. Chem. 2000,
65, 4938.
(2) Loesel, W.; Roos, O.; Schnorrenberger, G. U. S. Patent,
4694085, 1987; Chem. Abstr. 1988, 108, 204513.
(3) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. A. J.
Med. Chem. 1998, 31, 2097.
R4
=
OCOCF3
(4) Suehiro, M.; Greenberg, J. H.; Shine, C. Y.; González, C.;
Dembowski, B.; Reivich, M. Nucl. Med. Biol. 1996, 23, 407;
and references cited therein.
(5) (a) Bentley, K. Nat. Prod. Rep. 1998, 15, 341. (b) Bentley,
K. Nat. Prod. Rep. 2000, 17, 247. (c) Bentley, K. Nat. Prod.
Rep. 2001, 18, 341.
Scheme 4 (a) R3Li, -78 ºC, THF, 6 h; (b) TFA, CH2Cl2, r.t., 3 days.
(6) For a review on synthesis and biological properties of
Erythrinanes, see: Tsuda, Y.; Sano, T. In The Alkaloids:
Chemistry and Pharmacology, Vol. 48; Cordell, G. A., Ed.;
Academic Press: San Diego, 1996, Chap. 4, 249.
(7) (a) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T.
Heterocycles 1992, 33, 497. (b) Tsuda, Y.; Hosoi, S.;
Katagiri, N.; Kaneko, C.; Sano, T. Chem. Pharm. Bull. 1993,
41, 2087. (c) Sano, T.; Kamiko, M.; Toda, J.; Hosoi, S.;
Tsuda, Y. Chem. Pharm. Bull. 1994, 42, 197.
CH3O
N
O
CH3O
b
a
R3
H
2a,b
10a,b
H
11a R3 = CH3 (ee > 99%)
11b R3 = Bu (ee > 99%)
(8) (a) Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E.
Tetrahedron Lett. 1996, 33, 7841. (b) Manteca, I.; Etxarri,
B.; Ardeo, A.; Arrasate, S.; Osante, I.; Sotomayor, N.; Lete,
E. Tetrahedron 1998, 54, 12361.
(9) (a) Arai, Y.; Matsui, M.; Koizumi, T.; Shiro, M. J. Org.
Chem. 1991, 56, 1983. (b) Arai, Y.; Matsui, M.; Fujii, A.;
Kontani, T.; Ohno, T.; Koizumi, T.; Shiro, M. J. Chem. Soc.,
Perkin Trans. 1 1994, 25. (c) Aversa, M. C.; Barattucci, A.;
Bonaccorsi, P.; Gianneto, P. J. Org. Chem. 1997, 62, 4376.
(10) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990.
CH3O
CH3O
N
O
R3
1a R3 = CH3 (85%, ee > 99%)
1b R3 = Bu (80%, ee > 99%)
Scheme 5 (a) SmI2, HMPA, t-BuOH, THF, 1.5 h; (b) 560 °C,
1 mm Hg.
(11) For reviews on stereoselective Diels-Alder reactions of
sulfinyl derivatives, see: (a) Carreño, M. C. Chem. Rev.
1995, 95, 1717. (b) García Ruano, J. L.; Carretero, J. C.;
Carreño, M. C.; Martín Cabrejas, L. M.; Urbano, A. Pure
Appl. Chem. 1996, 68, 925.
(12) For some more recent examples, see, for instance:
(a) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Gianneto,
P.; Panzalorto, M.; Rizzo, S. Tetrahedron: Asymmetry 1998,
9, 1577. (b) Arai, Y.; Masuda, T.; Masaki, Y. J. Chem. Soc.,
Perkin Trans. 1 1999, 2165. (c) Carreño, M. C.; García-
Cerrada, S.; Urbano, A.; Di Vitta, C. J. Org. Chem. 2000, 65,
4355. (d) Carreño, M. C.; García Ruano, J. L.; Toledo, M. A.
Chem. Eur. J. 2000, 6, 288. (e) García Ruano, J. L.; Bercial,
F.; Fraile, A.; Martín Castro, A. M.; Martín, M. R.
Tetrahedron: Asymmetry 2000, 11, 4737.
Table Elimination of Chiral Auxiliary. Preparation of 11.
Entry
Substrate
2a
Product
11a
Yield (%)
1
2
3
4
96
86
83
83
10a
11a
2b
11b
10b
11b
In summary, we have shown that it is possible to obtain
chiral C-10b substituted 5,6-dihydropyrrolo[2,1-a]iso-
quinolines with high optical purity via diastereoselective
intramolecular -amidoalkylation reactions of -hydroxy-
(13) The absolute configuration of the sulfoxide was established
by correlation with related structures: Arai, Y.; Matsui, M.;
Koizumi, T. Synthesis 1990, 320; see also ref.9b.
Synlett 2002, No. 4, 593–597 ISSN 0936-5214 © Thieme Stuttgart · New York

596
I. González-Temprano et al.
LETTER
(14) Nuclear Overhauser effect difference spectroscopy and 1H-
1H decoupling experiments confirmed the stereochemistry
of isoquinolines. For instance, isoindoloisoquinoline 2a
(Figure 2) demonstrated an enhancement of the H-11, H-12
and H-6ax signals upon irradiation on C-12b methyl
1.25 (m, 2 H), 1.48 (s, 3 H), 1.60–1.72 (m, 6 H), 2.1 (d, J =
8.3 Hz, 1 H), 2.54 (dd, J = 16.2, 4.4 Hz, 1 H), 2.75 (d, J =
13.1 Hz, 1 H), 2.81–2.92 (m, 1 H), 3.07 (ddd, J = 13.1, 12.3,
4.8 Hz, 1 H), 3.21 (d, J = 13.1 Hz, 1 H), 3.32 (d, J = 3.6 Hz,
1 H), 3.37 (s, 1 H), 3.74–3.78 (m, 2 H), 3.81–3.89 (m, 1 H),*
3.82 (s, 3 H),* 3.89 (s, 3 H),* 4.18 (dd, J = 13.1, 6.3 Hz, 1
H), 6.33–6.37 (m, 1 H), 6.45–6.48 (m, 2 H), 6.60 (s, 1 H) (*:
partially overlapped signals); 13C NMR (CDCl3) 19.9, 20.4,
26.5, 27.0, 27.6, 30.5, 35.4, 38.3, 48.7, 44.9, 45.8, 46.5, 48.1,
50.2, 51.0, 52.5, 55.7, 56.2, 60.6, 75.4, 76.8, 107.4, 112.0,
124.1, 135.3, 135.8, 139.2, 147.9, 148.0, 168.4; MS (EI)
m/z (rel. intensity) 526 (M+ + 1, 2), 525 (M+, 1), 373(47),
325(19), 324(23), 310(16), 308(25), 307(100), 292(21),
290(27), 258(26), 206(16), 164(8), 119(35), 91(26).
10a (38 mg, 16%): [ ]D 23 +95.7 (1, CHCl3); IR (CHCl3):
2950, 1780, 1673 cm–1; 1H NMR (CDCl3) 0.86 (s, 3 H), 1.04
(s, 3 H), 1.48 (s, 3 H), 1.23–1.25 (m, 2 H), 1.58–1.92 (m, 5
H), 2.1 (d, J = 8.3 Hz, 1 H), 2.47 (dd, J = 16.0, 3.8 Hz, 1 H),
2.79 (ddd, J = 16.0, 12.3, 6.5 Hz, 1 H), 3.03 (td, J = 12.6, 4.4
Hz, 1 H), 3.12–3.23 (m, 2 H), 3.28 (s, 1 H), 3.52 (d, J = 3.6
Hz, 1 H), 3.59 (s, 1 H), 3.82–3.88 (m, 1 H),* 3.82 (s, 3 H),*
3.89 (s, 3 H),* 4.10 (dd, J = 13.1, 6.1 Hz, 1 H), 5.05 (dd, J =
7.4, 2.8 Hz, 1 H), 6.31–6.34 (m, 1 H), 6.45–6.49 (m, 2 H),
6.60 (s, 1 H) (*: partially overlapped signals); 13C NMR
(CDCl3) 19.6, 20.0, 26.3, 26.7, 27.6, 29.9, 35.7, 38.5, 46.7,
44.8, 45.3, 45.6, 49.2, 50.2, 50.4, 52.6, 55.7, 56.2, 60.7, 75.7,
82.0, 107.6, 111.7, 110.7, 124.0, 135.4, 136.2, 139.7, 147.8,
147.9, 155.6, 169.2; MS (EI) m/z (rel. intensity) 621 (M+, 6),
622 (M + 1, 3), 623 (M + 2, 1), 325(5), 324(100), 308(17),
307(18), 290(12), 258(15), 206(15), 164(13), 135(10),
119(52), 93(11), 91(20).
(8aS,9S,12R,12aS,12bR)-(+)-2,3-Dimethoxy-12b-methyl-
5,6,8a,9,12,12a-hexahydro-9,12-methaneisoindolin[2,3-
a]isoquinolin-8-one(11a). To a solution of 2a (100 mg, 0.2
mmol) in dry THF (5 mL), SmI2 (20 mL of a 0.1 M solution
in THF, 2 mmol), t-BuOH (0.2 mL, 2.1 mmol), and HMPA
(2.5 mL, 15 mmol) were added sequentially at r.t. The
resulting mixture was stirred at this temperature for 1.5 h,
and quenched by the addition of cold HCl (15 mL of a 1 M
solution). The organic layer was separated, and the aqueous
phase was extracted with CHCl3 (3 10 mL). The combined
organic extracts were washed with saturated Na2S2O3 (3 10
mL) and with brine (3 10 mL), dried (Na2SO4) and
concentrated in vacuo. Purification by flash column
hydrogens and vice versa. This fact, together with the
absence of NOE between C-12b methyl hydrogens and the
protons H-12a and H-13, confirms an R configuration for C-
12b. The rest of the NOE experiments carried out were fully
consistent with the proposed stereochemistry in each case.
nOe
nOe
H
6
H
N
O
H
11 H
CH3
12b
10
CH3O
CH3O
1
9 H
H
no
nOe
H
S
R1
O
2a
Figure 2
(15) See ref.9b For other reagents for reductive desulfinylation,
see, for instance: (a) Zn/HOAc: Rusell, G. A.; Mikol, V. J.
Am. Chem. Soc. 1966, 88, 5498. (b) Zn/NH4Cl: Holton, R.
A.; Crouse, D. J.; Williams, A. D.; Kennedy, R. M. J. Org.
Chem. 1987, 52, 2317. (c) Raney Ni/NaPH2O2: Node, M.;
Nishide, K.; Shigeta, Y.; Obata, K.; Shiraki, H.; Kunishige,
H. Tetrahedron 1997, 53, 12883.
(16) The enantiomeric excess of 11a,b and 1a,b was determined
in each case by CSP HPLC (Chiralcel OD, 20% hexane–2-
propanol, 0.4 mL/min) by comparison with the
corresponding racemates. The racemates were prepared by
an alternate procedure described in ref.8b. Representative
procedures and characterization data for 1a, 2a, 10a, 11a:
(8aR,9S,12R,12aS,12bR)-(+)-8a-[(1S,2R,4R,SS)-(2-
Hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-
yl)methylsulfinyl]-2,3-dimethoxy-12b-methyl-
5,6,8a,9,12,12a-hexahydro-9,12-methaneisoindolin[2,3-
a]isoquinolin-8-one(2a).
To a solution of the imide 3 (1.15 g, 2.2 mmol) in dry THF
(45 mL), MeLi (7.6 mL of a 0.66 M solution in pentane, 5
mmol) was added at –78 °C. The resulting mixture was
stirred at this temperature for 6 h, quenched by the addition
of saturated NH4Cl (20 mL), and allowed to warm to room
temperature. The organic layer was separated, and the
aqueous phase was extracted with CH2Cl2 (3 20 mL). The
combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to afford hydroxy lactam 9a (1.18 g,
99%), which was used without further purification.
To a solution of the so obtained hydroxy lactam 9a (203 mg,
0.4 mmol) in CH2Cl2 (10 mL), TFA (2.5 mL, 32.4 mmol)
was added and the resulting solution was stirred at room
temperature for 3 days. The reaction mixture was treated
with saturated aqueous NaHCO3, the organic layer was
decanted and the aqueous phase was extracted with CH2Cl2
(3 10 mL). The combined organic extracts were washed
with brine (2 10 mL), dried (Na2SO4) and concentrated in
vacuo. The resulting crude reaction mixture was purified by
column flash chromatography (silica gel, 60% hexane–ethyl
acetate), yielding two fractions.
chromatography (silica gel, ethyl acetate) afforded
isoindoloisoquinoline 11a (59 mg, 96%), whose
spectroscopic data are coincidental to those previously
reported for the racemate8b: [ ]D23 +202.8 (1.43, CHCl3); mp
(Et2O) 183–184 °C [Lit.8a racemate (Et2O) 158–160 °C]; 1H
NMR (CDCl3) 1.45 (s, 3 H),* 1.41–1.45 (m, 1 H),* 1.64 (d,
J = 8.3 Hz, 1 H), 2.44 (d, J = 11.9 Hz, 1 H), 2.96–2.99 (m,
2 H), 3.09–3.11 (m, 2 H), 3.23–3.25 (m, 2 H), 3.82 (s, 3 H),
3.90 (s, 3 H), 4.10–4.14 (m, 1 H), 6.21–6.23 (m, 2 H), 6.48
(s, 1 H), 6.65 (s, 1 H) (*: partially overlapped signals). The
enantiomeric excess was determined by CSP HPLC to be
> 99%, by comparison with the racemic mixture. Chiralcel
OD, 20% hexane–2-propanol, 0.4 mL/min; tr (ent-11a) =
18.5 min (< 1%); tr(11a) = 21.2 min (> 99%).
(10bR)-(+)-(-8,9-Dimethoxy-10b-methyl-5,6-
dihydropyrrolo[2,1-a]isoquinolin-3(10bH)-one(1a).
Isoindoloisoquinoline 11a (92 mg, 0.28 mmol) was heated at
560 °C under vacuum (1 mm Hg) for short periods of time
(10 min).18 The evolution of the reaction was monitored by
1H NMR, and the procedure was repeated until complete
evolution of starting material was observed. The crude
product was purified by column chromatography (silica gel,
80% hexane–EtOAc) (63 mg, 85%), whose spectroscopic
2a (101 mg, 51%): [
]
23 +117.9 (0.5, CHCl3); mp (Et2O–
D
pentane) 121–122 °C; IR (CHCl3): 3400, 2975, 1673, 1407
cm–1; 1H NMR (CDCl3) 0.60 (s, 3 H), 1.04 (s, 3 H), 1.23–
Synlett 2002, No. 4, 593–597 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective -Amidoalkylation Reactions of Hydroxylactams
597
data were coincidental to those previously reported for the
OD, 20% hexane–2-propanol, 0.4 mL/min; tr (ent-1a) = 14.5
min (< 1%); tr(1a) = 18.2 min (> 99%).
(17) For a review on applications of retro-Diels-Alder reactions
in stereoselective synthesis, see: Klunder, A. J. H.; Zhu, J.;
Zwanenburg, B. Chem. Rev. 1999, 99, 1163.
racemate.8b [ ]23D +201.4 (0.35, CHCl3); 1H NMR (CDCl3)
1.59 (s, 3 H), 2.65 (dd, J = 15.8, 3.9 Hz, 1 H), 2.85–2.99 (m,
1 H), 3.22 (td, J = 12.0, 4.5 Hz, 1 H), 3.83 (s, 3 H), 3.90 (s,
3 H), 4.4 (dd, J = 13.5, 6.3 Hz, 1 H), 6.10 (d, J = 5.5 Hz, 1
H), 6.59 (s, 1 H), 6.68 (s, 1 H), 7.34 (d, J = 5.9 Hz, 1 H). The
enantiomeric excess was determined by CSP HPLC to be
> 99%, by comparison with the racemic mixture. Chiralcel
(18) Continuous heating at 1 mm Hg for longer periods of time
resulted in decomposition of starting material.
Synlett 2002, No. 4, 593–597 ISSN 0936-5214 © Thieme Stuttgart · New York