Stereochemically controlled syntheses of indole-substituted dihydrofuran-2-ones and a pyrrolidin-2-one

Article abstract of DOI:10.1016/S0040-4039(00)01719-6

In order to obtain constrained analogues of tryptophane, five-membered lactams and lactones bearing 4-indolyl and 3-carboxylic groups were prepared in a completely diastereoselective manner, resulting in a trans relationship. Furthermore, the use of chira

Full text of DOI:10.1016/S0040-4039(00)01719-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9771–9775
Stereochemically controlled syntheses of indole-substituted
dihydrofuran-2-ones and a pyrrolidin-2-one
a
a
a,†
Michel Boisbrun, Arpa´d Kova´cs-Kulyassa, Laurent Jeannin, Janos Sapi,a Lo¨ıc Toupetb
´
and Jean-Yves Laronzea,*
aUMR CNRS 6013, Faculte´ de Pharmacie, Universite´ de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay,
F-51096 Reims, France
bUMR CNRS 6626, Universite´ de Rennes I, Baˆt 11A, Campus de Beaulieu, F-35042 Rennes, France
Received 20 July 2000; accepted 5 October 2000
Abstract
In order to obtain constrained analogues of tryptophane, five-membered lactams and lactones bearing
4-indolyl and 3-carboxylic groups were prepared in a completely diastereoselective manner, resulting in a
trans relationship. Furthermore, the use of chiral precursors in the synthesis yielded enantiomerically pure
compounds with three contiguous chiral centres. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: indoles; lactams; lactones; stereocontrol.
3-Amino-4-indolyl-dihydrofuran-2-ones and pyrrolidin-2-ones 1 (Fig. 1) can be considered as
constrained analogues of tryptophan1 and serotonin.2 They can also be useful building blocks
for the synthesis of various heterocycles exhibiting potent pharmacological activities on the
central nervous system3–5 or show antitumor activity.6,7
Figure 1.
* Corresponding author. Fax: +33-3/26 91 80 29; e-mail: jy.laronze@univ-reims.fr
†
Present address: Peptisyntha, 33 rue du Prince Albert, B-1050 Brussels, Belgium.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01719-6

9772
In the continuation of our programme on the synthesis of non-natural tryptophan deriva-
tives,8 we recently reported9 a short approach to pyrrolidones 5 based on simple functional
group transformations starting from compound 3, as depicted in Scheme 1. Since 3 is racemic,
and the ring opening of the Meldrum’s acid core to 4 was not stereoselective, 5 was isolated as
a separable mixture of racemic diastereomers.
Scheme 1.
In this regard, it was worth studying whether intramolecular nucleophilic attack on the cyclic
malonic ester residue would improve the stereochemical outcome of the formation of the
5-membered ring. Herein, we wish to describe our preliminary results concerning a stereoselec-
tive route to compounds of general formula 2.
Condensation of indole, Meldrum’s acid, and protected 2-hydroxyacetaldehyde (6a)10 or
2-aminoacetaldehyde (6b)9 gave rise to racemic trimolecular adducts 7a and 7b, respectively
(Scheme 2). Removal of the protecting group by hydrogenolysis, followed by spontaneous
intramolecular ring closure afforded 2a and 2b11 in one-pot reactions. In both cases, cyclisation
resulted in the stereoselective formation of the respective ( )-trans disubstituted ring, while no
cis diastereoisomer could be isolated. The trans relative stereochemistry was assigned with the
aid of NOE experiments‡ and of comparison with previous results.§
Scheme 2. Conditions: (i) CH3CN, cat.
D,L-proline, 75% (6a), 65% (6b); (ii) EtOH, H2, Pd/C, 90% (2a), 80% (2b)
Nucleophilic attack of the internal hydroxy or amino groups seems to be dictated by steric
factors. Fig. 2 shows the transition-state of the favoured equatorial approach, in which the
bulky indole moiety is most remote from the carbonyl groups, leading to trans disubstituted
products.
Knowing that the ring closure proceeds with trans selectivity, it seemed attractive to
investigate how the first chiral centre can be created in the trimolecular condensation. For this
purpose, 2,3-O-isopropylidene-
-glyceraldehyde13 [(R)-8], as chiral template, was condensed
D
with indole and Meldrum’s acid, affording the adduct 914 as the sole diastereomer (Scheme 3).
‡ A 6% NOE between the ‘malonic’ proton and those at positions 2 and 4 of the indole moiety was observed.9,12
1
§ The H NMR spectrum of 2b showed a similar pattern to trans-5.9

9773
Figure 2.
Scheme 3. Conditions: (i) CH3CN, cat.
D,L-proline, 75%; (ii) CH3CN, 10% HCl, 83%
The absolute configuration of the newly formed asymmetric carbon atom in 9 could not be
determined by the usual spectroscopic methods. Hydrolysis of the isopropylidene protecting group
followed by spontaneous cyclisation led to the lactone 2c15 in a regio- and stereoselective manner,
as was elucidated from its 1H and 13C spectra. The absolute stereochemistry was assigned by single
crystal X-ray analysis16 (Fig. 3), which also permitted us to deduce the configuration of the newly
created chiral carbon atom in 9. Concerning the selective formation of this centre, according to
recent work published by Ortun˜o and co-workers,17 we assume that indole attacks the Si face of
the Knoevenagel adduct formed from Meldrum’s acid and the protected glyceraldehyde (Fig. 4).
This two-step sequence was also performed using 2,3-O-isopropylidene- -glyceraldehyde
L
[(S)-8]18 giving, as was expected, (R,R)-9 and (R,R,R)-2c, whose physical and spectral character-
istics were identical to those of their enantiomers, except for their specific rotations.19
Figure 3.

9774
Figure 4.
In summary, a convenient and stereoselective procedure has been worked out for the synthesis
of indolyl-substituted lactams and lactones of type 2. We have shown that the chirality of the
glyceraldehydes ensured complete enantiocontrol of the trimolecular condensation and in this
way that of three contiguous chiral centres in 2c. Further work involving other chiral aldehydes
as well as the transformation of compounds 2 into 1 is in progress in our laboratory.
Acknowledgements
This work was financed by the ADIR Company (Laboratoires Servier) and by the CNRS
(Centre National de la Recherche Scientifique) to which our gratitude is expressed. We thank
C. Peterman and P. Sigaut for spectroscopic measurements. Special thanks are due to Drs. G.
Bird (Astra Zeneca) and Cs. Nemes for help with the text.
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1
data: Compound 2a: mp 157°C; IR (KBr) 3410, 1771, 1738 cm−1; H NMR (DMSO-d6) l 4.01 (d, J=10.8 Hz,
1H), 4.35 (m, 2H), 4.78 (m, 1H), 7.04 (t, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.40
(d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 11.11 (s, 1H), 13.2 (br s, 1H); HRMS (EI): M+ found 245.0679.
C13H11NO4 requires: 245.0685. Compound 2b: mp 195°C; IR (KBr) 3385, 1721, 1684 cm−1; 1H NMR (DMSO-d6)
l 3.39 (t, J=9.0 Hz, 1H), 3.52 (d, J=10.0 Hz, 1H), 3.75 (t, J=9.0 Hz, 1H), 4.18 (m, 1H), 7.02 (t, J=8.0 Hz,
1H), 7.12 (t, J=8.0 Hz, 1H), 7.30 (s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 10.88
(s, 1H), 12.5 (br s, 1H); HRMS (EI): M+ found: 244.0848. C13H12N2O3 requires: 244.0840.

9775
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14. Compound (S,S)-9: mp 65°C; [h]D −33 (c=1.22, CHCl3); IR (CH2Cl2) 3408, 1773, 1740 cm−1
;
1H NMR
(DMSO-d6) l 1.28 (s, 3H), 1.32 (s, 3H), 1.39 (s, 6H), 3.20 (s, 1H), 3.65 (t, J=7.0 Hz, 1H), 3.95 (t, J=7.0 Hz,
1H), 4.12 (d, J=10.0 Hz, 1H), 5.19 (m 1H), 6.87 (t, J=8.0 Hz, 1H), 6.98 (t, J=8.0 Hz, 1H), 7.18 (d, J=2.0 Hz,
1H), 7.28 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 10.52 (s, 1H); HRMS (EI): M+ found 373.1549.
C20H23NO6 requires: 373.1525.
15. Compound (S,S,S)-2c: mp 82°C; [h]D +139 (c=0.82, MeOH); IR (KBr) 3410, 1769, 1736 cm−1 1H NMR
;
(DMSO-d6) l 3.24 (dd, J=2.4 and 12.3 Hz, 1H), 3.40 (dd, J=1.8 and 12.3 Hz, 1H), 4.28 (d, J=12.0 Hz, 1H),
4.49 (dd, J=8.1 and 12.0 Hz, 1H), 5.00 (br s, 1H), 5.08 (m, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H),
7.30 (d, J=2.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 11.10 (s, 1H); HRMS (FAB): M+
found: 275.0800. C14H13NO5 requires: 275.0794.
,
16. Crystallographic data for (S,S,S)-2c: C14H13NO5; orthorhombic; cell parameters (T=20°C) a=7.837(4) A,
b=12.003(3) A, c=14.732(10) A; V=1386(1) A−3; space group: P212121, Z=4, R=0.033, Rw=0.076 for
refinements based on 1451 observed [I>2.0|(I)] reflections. Crystallographic data (excluding structure factors) for
the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-144787. Copies of the data can be obtained, free of charge, on application
to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, [Fax: +44-1223/336-033; e-mail: deposit@
ccdc.cam.ac.uk.
,
,
,
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19. Compound (R,R)-9: [h]D +35 (c=1.27, CHCl3). Compound (R,R,R)-2c: [h]D −137 (c=0.84, MeOH).
.
.