Stereoselective dihydropyrido(2,1-a)isoindolone synthesis via diastereodivergent Heck cyclisations on chiral 1,4-dihydropyridines

Article abstract of DOI:10.1016/S0040-4039(00)02010-4

A stereoselective dihhydro(2,1-a)isoindolone synthesis is described via diastereodivergent cyclisations by using reductive or non-reductive Heck reactions on chiral 1,4-dihydropyridines.

Full text of DOI:10.1016/S0040-4039(00)02010-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 589–592
Stereoselective dihydropyrido(2,1-a)isoindolone synthesis via
diastereodivergent Heck cyclisations on chiral
1,4-dihydropyridines†
Christophe Pays and Pierre Mangeney*
Laboratoire de Chimie des Organo-Ele´ments associe´ au CNRS, Universite´ P. et M. Curie, 4, Place Jussieu,
F-75252 Paris Cedex 05, France
Received 10 October 2000; accepted 7 November 2000
Abstract—A stereoselective dihydropyrido(2,1-a)isoindolone synthesis is described via diastereodivergent cyclisations by using
reductive or non-reductive Heck reactions on chiral 1,4-dihydropyridines. © 2001 Elsevier Science Ltd. All rights reserved.
We have already disclosed the synthesis of polycyclic
nitrogen heterocycles by regio- and diastereoselective
cyclisations of chiral N-acyl-1,4-dihydropyridines
according to Scheme 1.
II (syn) or III (anti). In II there is no possibility of syn
b-elimination of XPdH therefore a tandem cyclisation–
hydride capture4 would give the [C4-(R), C6-(R)] adduct
IV. If the cyclisation was to occur in an anti manner
affording III, a syn b-elimination would give VI and then
the [C4-(S), C6-(S)] adduct VII via a diastereoselective
(anti) hydrogenation. An hydride capture performed, if
it is possible, on III would give the [C4-(R), C6-(S)]
adduct V. According to these possibilities, as shown in
Scheme 2, three different diastereomers could be
obtained. We wish to report here the results obtained
during this study.
As shown below, a syn (compared to the C-4 substituent)
cyclisation onto the C-2 or C-6 was observed under
radical conditions, while an anti cyclisation onto the C-6
was obtained via a Pictet–Spengler reaction.1 As part of
our effort to extend the synthetic potentiality of such
1,4-dihydropyridines, we decided to study the possibility
of a stereoselective synthesis of the isoindolone2 ring
system from I (C4-(R), Scheme 2), using a Heck cyclisa-
tion.3 If the cyclisation is regioselective onto the C-6ꢀC-5
double bond (e.g. the less substituted one) and according
to the two possible stereochemistries (syn or anti, Scheme
2), we could obtain the two diastereomeric intermediates
The dihydropyridine 1 was prepared, in 85% yield and
95% de, from the aminal 2 (S,S) by addition of MeCu
in the presence of 2-iodobenzoyl chloride. An acidic
hydrolysis afforded the aldehyde 3 (Scheme 3).1
Scheme 1.
Keywords: dihydropyridines; Heck reaction; isoindolone synthesis.
* Corresponding author. Tel.: +01 44 27 55 68; fax: +0144277567; e-mail: mangeney@moka.ccr.jussieu.fr
†
Dedicated to Professor J. Normant on the occasion of his 65th birthday.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02010-4

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C. Pays, P. Mangeney / Tetrahedron Letters 42 (2001) 589–592
In the presence of a catalytic (5%) amount of Pd(OAc)2,
AcOK in DMF (90°C, 2h)5 the dihydropyridine 1 was
regioselectively converted into 4 (60% yield, 95% de,
1H/NMR). The absolute configuration of this com-
pound was determined by X-ray analysis6 (Fig. 1) and
found to be C-6(S). Therefore, 4 resulted from an anti
carbopalladation then a syn b-elimination and an iso-
merisation of the double bond. Acidic hydrolysis of the
aminal group in 4 afforded the aldehyde 5 (90% yield).
dinium formate, gave the two diastereomeric products 6
(94% de) and 7 (95% de) in a 7/3 ratio. These two
compounds were separated by chromatography.
The cis relationship for the C6-H and the C4-Me sub-
stituents in 6 was determined by 1H NMR (NOE,
Scheme 4). Aminals 6 and 7 were respectively converted
into the aldehydes 8 and 9 by acidic hydrolysis. The
relative configuration of 9 was determined by chemical
correlation from 10, which was obtained by
a
A tandem cyclisation–hydride capture performed on 1,
in the presence of 5% of Pd(OAc)2(PPh3)2 and piperi-
diastereoselective hydrogenation on the less hindered
face of 5 (Scheme 5).
Scheme 2.
Scheme 3.
Figure 1.
Figure 2.

C. Pays, P. Mangeney / Tetrahedron Letters 42 (2001) 589–592
591
Scheme 4.
Scheme 5.
Scheme 6.
1
The H NMR spectra of 9 and 10 were identical, but
the R,S and S,S configurations, with ee=94% and 95%,
by using non-reductive or reductive Heck cyclisations.
Such a result was totally unexpected and detailed mech-
anistic considerations will be reported in due course.
Nevertheless, it seems synthetically useful to be able to
change the stereochemistry of an intramolecular Heck
reaction.
different from the 1H NMR of 8. Therefore, since 8 was
obtained from 6 (cis relationship for C6-H and C4-Me),
we postulate that the C6-H and C4-Me relationship in 9
and 10 was trans. Surprisingly, the signs of their optical
rotation were opposite, showing that these two prod-
ucts were enantiomers. The absolute configuration of 6
was determined by X-ray analysis6 (Fig. 2) and found
to be C-4(S) and C-6(R). Therefore the two
diastereomers 6 and 7, obtained by a tandem cyclisa-
tion–hydride capture, were the result of a syn carbopal-
ladation and a partial epimerisation of the C-4 methyl
group.
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In conclusion, the cyclisation occurs selectively onto the
C-5ꢀC-6 double bond, but the stereochemistry is
strongly dependent on the reaction conditions. As sum-
marized in Scheme 6, starting from the same dihy-
dropyridine 1, it is possible to prepare selectively the
dihydropyridoisoindolones 8 or 10 having, respectively,

592
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