Enantioselective synthesis of pyrrolo[2,1-a]isoquinolones via stereocontrolled N-acyliminium ion cyclisations

Article abstract of DOI:10.1016/S0040-4039(00)02319-4

Stereocontrolled N-acyliminium ion cyclisation of L-DOPA derived succinimide 5 has been investigated. Addition of organolithiums to chiral non-racemic 5 yields oxoamides, which are cyclised diastereoselectively upon treatment with BF₃·OEt₂, to afford 5,10b-trans pyrroloisoquinolones in moderate yields and high ee (99%).

Full text of DOI:10.1016/S0040-4039(00)02319-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1511–1513
Enantioselective synthesis of pyrrolo[2,1-a]isoquinolones via
stereocontrolled N-acyliminium ion cyclisations
Eva Garc´ıa, Sonia Arrasate, Ainhoa Ardeo, Esther Lete* and Nuria Sotomayor
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencias, Universidad del Pa´ıs Vasco, Apdo. 644-48080, Bilbao, Spain
Received 8 November 2000; accepted 16 December 2000
Abstract—Stereocontrolled N-acyliminium ion cyclisation of L-DOPA derived succinimide 5 has been investigated. Addition of
organolithiums to chiral non-racemic 5 yields oxoamides, which are cyclised diastereoselectively upon treatment with BF3·OEt2,
to afford 5,10b-trans pyrroloisoquinolones in moderate yields and high ee (99%). © 2001 Elsevier Science Ltd. All rights reserved.
N-Acyliminium ion cyclisation1 is a valuable car-
bonꢀcarbon bond formation method for the stereocon-
trolled synthesis of nitrogen heterocycles which has
been applied to the preparation of enantiomerically
enriched compounds.2 It has been shown that
intramolecular reactions of cyclic N-acyliminium ions
with p-nucleophiles proceeds stereoselectively due to
steric control by the substituents already present in the
ring3 or along the chain connecting the p-nucleophiles
and the nitrogen atom.4
quinolines.6 In this paper, we wish to report the enan-
tioselective synthesis of 5,10b-trans pyrroloiso-
quinolones from an enantiomerically pure N-phenethyl-
imide 5. The key step would be the stereocontrolled
cyclisation of an N-acyliminium ion, which bears a
stereogenic centre a to the nitrogen atom.
Imide 5 was prepared from
tional group manipulation, as outlined in Scheme 1.
Thus, protection of the amino group of -DOPA, fol-
L-DOPA by standard func-
L
lowed by methylation yielded ester 1, which was sub-
mitted to successive steps of LiAlH4 reduction,
protection of the resulting primary alcohol and hydrol-
ysis of Boc amide to afford amine 4. Sequential treat-
ment of this amine with succinic anhydride followed by
Ac2O and NaOAc yielded succinimide 5. Thus, this
We have described an efficient procedure for the syn-
thesis of several types of isoquinoline alkaloids based
on N-acyliminium ion chemistry.5 Recently, we have
investigated the stereoselectivity of intramolecular reac-
tions of cyclic N-acyliminium ions with a substituent
adjacent to the iminium carbon, which has led to the
diastereoselective synthesis of 1,10b-cis thiazoloiso-
imide was prepared in high overall yield from L-DOPA
(50%), and without epimerisation of the stereogenic
CH3O
CH3O
CO2CH3
OR
1. (Boc)2O
2. SO4Me2
LiAlH4
L-DOPA
NHBoc
CH3O
NHBoc
CH3O
1 (92%)
2 R = H (87%)
TBDPSCl
3 R = TBDPS (95%, 99%ee)
O
O
O
CH3O
CH3O
CH3O
TFA
1.
OTBDPS
OTBDPS
NH2
N
O
2. Ac2O, AcONa
O
CH3O
4 (86%)
5 (75%, 99% ee)
Scheme 1.
* Corresponding author. Fax: 34 944648500; e-mail: qopleexe@lg.ehu.es
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02319-4

1512
E. Garc´ıa et al. / Tetrahedron Letters 42 (2001) 1511–1513
CH3O
CH3O
OTBDPS
O
OR'
O
BF3•Et2O
RLi
N+
HN
5
CH3O
O
CH3O
R
R
6a R = CH3
6b R = n-Bu
12%
CH3O
CH3O
5
H3CO
OCH3
CH3
OH
O
7%
10b
N
R
H
H
1
N
no noe
7a R = CH3 (36%, 99% ee)
7b R = n-Bu (34%, 99% ee)
H
OH
O
7a
Scheme 2.
O
OCH3
OCH3
N+
OR'
R
H3CO
7 (5S,10bS)
7 (5S,10bR)
X
R
H3CO
R'O
N+
B (Si attack)
O
A (Re attack)
Figure 1.
centre, as imide 5 showed an enantiomeric excess equal
to the starting amino acid (99% ee), determined by
chiral phase HPLC.7
attack of the aromatic onto the N-acyliminium ion. The
stereochemical results are consistent with a late chair-
like transition state, in which the substituent in C-5 is
placed in a pseudo-equatorial disposition. Attack of the
aromatic ring onto the Re face of the N-acyliminium
ion leads to the observed stereochemistry, in which the
substituent in 10b (Me or Bu) assumes a pseudo-axial
position (A, Fig. 1). This stereochemical result is in
sharp contrast with related examples described in the
literature. According to Hart’s model, the most
favoured transition state would minimise A(1,3) strain.10
Thus, for intramolecular cyclisations of p nucleophiles
on the N-acyliminium ion with substituents adjacent to
the nitrogen atom, an axial orientation is preferred to
avoid A(1,3) strain between the substituent and the
carbonyl of the N-acyl group.2 This results in the
preferred formation of cis diastereomers of, for
instance, 5-phenyltetrahydro[2,1-a]isoquinolones,4b 5-
aryl-10b-butyltetrahydro[2,1-a]isoquinolones,11 indolizi-
dines,12 b-carboline derivatives13 or polycyclic isoindoli-
none derivatives.14 However, in our case, a balance
between A(1,3) strain and severe syn-axial 1,3 interac-
tions in transition state B, that would lead to a cis dia-
stereomer, favours the pseudo-equatorial disposition
for the C-5 substituent in the transition state A, leading
to 7a,b (Fig. 1). Similar effects have been described
for related structures that led to reversal of dia-
Succinimide 5 was treated with organolithiums (MeLi
or BuLi) to afford the corresponding oxoamides 6a,b.
Cyclisation of these oxoamides was accomplished with
8
BF3·Et2O in CH2Cl2 to afford pyrroloisoquinolones
7a,b, in which hydrolysis of the TBDPS group had also
occurred, in moderate overall yields. Cyclisation was
stereoselective, and the resulting pyrroloisoquinolones
were isolated as single 5,10b-trans diastereomers, not
detecting the presence of the corresponding cis
1
diastereomers. The stereochemistry was deduced by H
NMR. The J values of the ABX system formed by H-5
and H-6 protons indicate that H-5 is in a pseudo-axial
position. Besides, NOE difference spectroscopy showed
an enhancement between H-5 and the substituent in
10b (Me or Bu), as shown in Scheme 2 for 7a. These
data are consistent with a preferred half-chair confor-
mation in which the substituents in C-10b and in C-5
are in pseudo-axial and pseudo-equatorial positions,
respectively. Thus, the configuration was assigned as
5S,10bS and both pyrroloisoquinolones were isolated
with high enantiomeric purity (99%).9
The stereochemical outcome of the cyclisation may be
explained as a result of conformational factors in the
transition state, being the rate determining step of the
stereoselectivity as
a result of competing steric
interactions.4d

E. Garc´ıa et al. / Tetrahedron Letters 42 (2001) 1511–1513
1513
In conclusion, a stereoselective synthesis of enantiomer-
ically pure pyrrolo[2,1-a]isoquinolones via tandem
organolithium addition–N-acyliminium ion cyclisation
has been achieved. Of particular interest is the stereo-
control in the cyclisation step that leads to the 5,10b-
trans diastereomers.
1996, 37, 6193–6196; (c) Collado, M. I.; Manteca, I.;
Sotomayor, N.; Villa, M. J.; Lete, E. J. Org. Chem. 1997,
62, 2080–2092.
6. Osante, I.; Collado, M. I.; Lete, E.; Sotomayor, N.
Synlett 2000, 101–103.
7. Determined by chiral phase HPLC using a Chiralcel OD
column, 7% hexane/2-propanol, 1 mL/min.
8. All compounds gave satisfactory spectroscopic and ana-
lytical data. Typical procedure for 7a: To a solution of
succinimide 5 (270 mg, 0.51 mmol) in dry THF (10 mL),
MeLi (2 mL of a 1.0 M solution in diethyl ether, 2 mmol)
was added at −78°C and the resulting solution was stirred
at this temperature for 6 h. The reaction was quenched
by the addition of H2O (5 mL) and allowed to warm to
20°C. Standard work-up afforded the corresponding
Acknowledgements
Financial support from Gobierno Vasco (PI-1999-165)
and Universidad del Pa´ıs Vasco is gratefully acknowl-
edged. We also thank the Departamento de Educacio´n,
Universidades e Investigacio´n (Gobierno Vasco) and
M.E.C. for grants.
1
oxoamide 6a as a yellowish oil. [6a: H NMR (l, ppm):
1.11 (s, 9H), 2.14 (s, 3H), 2.22–2.38 (m, 2H), 2.67–2.74
(m, 2H), 2.86 (d, J=7.1 Hz, 2H), 3.60–3.62 (m, 2H), 3.79
(s, 3H), 3.84 (s, 3H), 4.10–4.21 (m, 1H), 5.87 (d, J=8.7
Hz, 1H), 6.67–6.75 (m, 3H), 7.37–7.45 (m, 6H), 7.60–7.65
(m, 4H)]. Without further purification, 6a was dissolved
in dry CH2Cl2 (10 mL), BF3·Et2O (0.76 mL, 6.2 mmol)
and the reaction mixture was heated under reflux for 4
days. After addition of aqueous saturated NaHCO3 (5
mL), standard work-up followed by flash column chro-
matography (silica gel, AcOEt) afforded (5S,10bS)-5-
hydroxymethyl-8,9-dimethoxy-10b-methyl-1,5,6,10b-tetra-
hydropyrrolo[2,1-a]isoquinolin-3[2H]-one (7a) (54 mg,
36%): ee 99%; [h]D20 −203 (c=0.046, CH2Cl2); mp 124–
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126°C (n-pentane). IR (KBr): 3392, 1654 cm−1; H NMR
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