Synthesis of chiral 2′,3′-pyranone(pyrrolidinone)-fused tryptamines

Article abstract of DOI:10.1016/S0040-4039(02)02537-6

Chiral pyrano- and pyrrolidino-fused tryptamines were prepared by a diasteroselective trimolecular condensation between indole, Garner's aldehyde and Meldrum's acid, followed by selective functional group transformations.

Full text of DOI:10.1016/S0040-4039(02)02537-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 221–223
Synthesis of chiral 2%,3%-pyranone(pyrrolidinone)-fused
tryptamines
†
´
Emmanuel Dardennes, Arpa´d Kova´cs-Kulyassa, Andrea Renzetti, Janos Sapi* and
Jean-Yves Laronze
UMR CNRS 6013 ‘Isolement, Structure, Transformations et Synthe`se de Produits Naturels’, IFR 53 ‘Biomole´cules’ Faculte´ de
Pharmacie, Universite´ de Reims-Champagne-Ardenne, 51 rue Cognacq-Jay, F-51096 Reims Cedex, France
Received 24 October 2002; accepted 13 November 2002
Abstract—Chiral pyrano- and pyrrolidino-fused tryptamines were prepared by a diasteroselective trimolecular condensation
between indole, Garner’s aldehyde and Meldrum’s acid, followed by selective functional group transformations. © 2002 Elsevier
Science Ltd. All rights reserved.
The trimolecular condensation between indole, alde-
hydes and Meldrum’s acid proved to be a versatile
method for the preparation of conformationally con-
strained b-substituted tryptophans.1
followed by selective functional group transformations
strategy (Scheme 2).
Such chiral, heterocycle fused tryptamines can be con-
sidered as valuable intermediates for the preparation of
functionalized, conformationally restricted serotonin3
and b-carboline4 analogs of biological interest.
When a chiral aldehyde, bearing a masked nucleophile
function (e.g. 2,3-O-isopropylidene-
was used, trimolecular condensation and a subsequent
deprotection–spontaneous cyclization sequence
D-glyceraldehyde)
In accord with our synthetic objectives Garner’s alde-
hyde 35 and its modified analog 4,6 both readily avail-
afforded the corresponding lactone acid (Scheme 1, B:
X=Y=O) enabling the creation of two novel stereo-
centers with complete diastereocontrol.2
able from L-serine, were chosen as chiral aldehydes.
Trimolecular condensation of indole 5, with Meldrum’s
acid 6, and Garner’s aldehyde 3, under standard condi-
tions,7 smoothly afforded the corresponding adduct 7,8
isolated by flash chromatography in 90% yield. 1H
In continuation of our program toward non-natural
tryptophan, tryptamine derivatives, we decided to
investigate the control of newly created stereocenters by
using orthogonally protected bifunctional chiral alde-
hydes. Depending on the conditions of deprotection
chemoselective internal nucleophile ring opening of the
Meldrum’s acid core could be envisaged (Scheme 1).
Herein, we disclose an efficient enantioselective access
to pyrano-
1
and pyrrolidino ring-substituted
tryptamines 2, based on a trimolecular condensation,
Keywords: multicomponent reaction; trimolecular condensation; Gar-
ner’s aldehyde; diastereoselective synthesis; chiral tryptamine deriva-
tives.
* Corresponding author. Tel.: +33-(0)326-918-022; fax: +33-(0)326-
918-029; e-mail: janos.sapi@univ-reims.fr
† Graduate student, on leave from the Faculty of Pharmacy, Univer-
sity of Chieti, Italy.
Scheme 1.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02537-6

222
E. Dardennes et al. / Tetrahedron Letters 44 (2003) 221–223
The absolute configuration of the newly created stereo-
center was determined at a later stage of the synthesis,
whereas the observed good diasteroselectivity could
result from a selective Re face approach of indole on
the Knoevenagel adduct (Fig. 1).
Similarly, modified Garner’s aldehyde 4, under the
same conditions, gave the appropriate adduct
8
diastereoselectively (diastereomer ratio 95:5) in 68%
yield.
Initially, selective isopropylidene deprotection of 7 was
attempted in methanol containing catalytic amount of
p-TsOH. After diazomethane-assisted esterification of
the intermediate lactone acid 9, diastereomerically pure
Nb-protected pyrano-annulated tryptamine 19 was iso-
lated. For its formation an internal nucleophile attack
of the primary alcohol on the Meldrum’s acid moiety
could be accounted. By longer heating in aqueous
acetic acid the decarboxylated counterpart 10 was also
prepared in 82% yield.
Scheme 2.
The configuration of 1 was determined by usual combi-
nation of NMR experiments. The observed coupling
constant, JH-3–JH-4=11.6 Hz in 1 was in accordance
with the H-3/H-4 trans relative stereochemistry, while
the absolute configuration of C-4 carbon, created dur-
ing the trimolecular condensation, was evidenced by
NOE measurements. The strong interaction between
irradiated NH and H-4, H-6 protons supported all
equatorial positions for the three substituents and (R)
absolute configuration of C-4 carbon (Fig. 2).
Treatment of 7 in boiling methanol–HCl led to
diastereomerically pure lactam ester 11, isolated by
chromatography in 73% yield. Its formation can be
explained by a full deprotection, selective internal nitro-
gen nucleophile ring closure sequence, followed by
esterification of the resulting carboxylic acid.
Similarly, deprotection of the Cbz group by
hydrogenolysis in ethanol containing acetic acid led to
the same lactam ester 11, isolated in 63% yield after
methylation with diazomethane. The preferred lactami-
sation over lactonisation permitted to establish stereo-
Scheme 3. Reagents and conditions: (i) CH3CN,
D,L-proline;
(ii) CH3OH, p-TsOH(cat); (iii) CH2N2, ether; (iv) AcOH–H2O,
reflux; (v) from 7: (a) CH3OH–HCl, reflux, (b) Et3N; (vi)
from 8: H2, Pd–C, EtOAc, AcOH; (vii) (a) TFA, CH2Cl2, (b)
Et3N; (viii) TBDMSCl, imidazole, CH2Cl2, DMF; (ix) (a)
KOHaq, THF, 0°C, (b) citric acid; (x) (a) DPPA, Et3N, (b)
BnOH, THF, reflux; (xi) H2, Pd–C, EtOAc.
Figure 1.
NMR analysis of 7 showed that the condensation step
underwent with a high (>90%) diastereoselectivity
(Scheme 3).
Figure 2. NOE measurements of 1.

E. Dardennes et al. / Tetrahedron Letters 44 (2003) 221–223
223
chemical correlation between the pyrano- and pyrro-
lidino-substituted series. Indeed, TFA-mediated cleav-
age of NBoc protection of 1 of known stereochemistry
afforded the formerly prepared lactam ester 11. Its
depicted stereochemistry was confirmed on the basis of
NOE experiments.
3. For some fused tryptamine derivatives, see: (a) Macor, J.
E.; Ryan, K. Heterocycles 1990, 31, 1497–1504; (b)
Schlecht, M. F.; Tsaroushtsis, D.; Lipovac, M. N.;
Debler, E. A. J. Med. Chem. 1990, 33, 386–394; (c)
Ghosh, A.; Wang, W.; Freeman, J. P.; Althaus, J. S.; Von
Voigtlander, P. F.; Scahill, T. A.; Mizsak, S. A;
Szmuszkovicz, J. Tetrahedron 1991, 47, 8653–8662; (d)
Ezquerra, J.; Pedregal, C.; Lamas, C.; Pastor, A.;
Alvarez, P.; Vaquero, J. J. Tetrahedron Lett. 1996, 37,
683–686.
Prior to the classical conversion of carboxylic acid into
carbamate some functional group transformations, e.g.
protection of the primary alcohol to afford 12, followed
by hydrolysis of the ester function, were achieved. Acid
function of 13 was transformed into carbamate 14 by
diphenylphosphoryl azide assisted acyl azide formation,
followed by Curtius rearrangement in the presence of
benzyl alcohol, providing benzyl carbamate 14 in 80%
overall yield. Final deprotection of 14 by hydrogenoly-
sis led almost quantitatively to the aimed pyrrolidino
tryptamine 2.10
4. For some selected 3,4-annulated (tetrahydro)-b-carboli-
nes, see: (a) Dubois, L.; Dorey, G.; Potier, P.; Dodd, R.
H. Tetrahedron: Asymmetry 1995, 6, 455–462; (b)
Nyerges, M.; Rudas, M.; Bitter, I.; To3 ke, L.; Sza´ntay, C.,
Jr. Tetrahedron 1997, 53, 3269–3280; (c) Ezquerra, J.;
Pedregal, C.; Lamas, C.; Pastor, A.; Alvarez, P.;
Vaquero, J. J. Tetrahedron 1997, 53, 8237–8248; (d)
Teller, S.; Eluwa, S.; Koller, M.; Uecker, A.; Beckers, T.;
Baasner, S.; Bo¨hmer, F.-D.; Mahboobi, S. Eur. J. Med.
Chem. 2000, 35, 413–427.
In conclusion, a highly enantioselective synthesis, based
on a trimolecular condensation as a key-step, has been
developed for the preparation of pyrano- and pyrro-
lidino-fused tryptamines (R,R,R)-1 and (S,S,R)-2. We
have shown that the chirality of the Garner’s aldehyde
ensured a complete and predictable enantiocontrol of
the two newly created stereocenters. Application of
functionalized tryptamines (1 and 2) to the synthesis of
biologically active polycyclic compounds is in progress.
5. (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52,
2361–2364; (b) Dondoni, A.; Perrone, D. Org. Synth.
1999, 77, 64–77.
6. Evans, P. A.; Holmes, A. B.; Russell, K. J. Chem Soc.,
Perkin Trans. 1 1994, 3397–3408.
7. Oikawa, Y.; Hirasawa, O.; Yonemitsu, O. Tetrahedron
Lett. 1978, 19, 1759.
8. All new compounds gave satisfactory spectral data.
1
Selected data for 7: [h]2D3 −1 (c 3.66, CH2Cl2); H NMR
(C6D6, 343 K): l 1.20 (s, 3H), 1.47 (s, 3H), 1.71 (s, 9H),
1.83 (s, 3H), 2.05 (s, 3H), 4.17 (dd, 1H, J=9.3, 6.3 Hz),
4.46 (s, 1H), 4.98 (brs, 1H), 5.12 (brs, 1H), 5.34 (d, 1H,
J=4.0 Hz), 7.38–7.52 (m, 4H), 7.86 s, 1H), 8.32 (d, 1H,
J=5.2 Hz).
Acknowledgements
The authors thank the ‘Ministe`re de l’Education
Nationale, de la Recherche et de la Technologie’ for a
Ph.D. fellowship to E.D. A.R. thanks the EU for an
Erasmus-Socrates studentship. Spectroscopic measure-
ments by P. Sigaut (MS) and C. Petermann (NMR) are
gratefully acknowledged.
9. Selected data for (R,R,R)-1: [h]2D2 −19 (c 1.00, CHCl3);
mp 147–149°C; 1H NMR (acetone-d6): l 1.26 (s, 9H),
3.51 (s, 3H), 3.95 (dd, 1H, J=11.6, 8.6 Hz), 4.22 (d, 1H,
J=11.6 Hz), 4.30–4.38 (m, 2H), 4.63 (dd, 1H, J=10.8,
3.8 Hz), 6.46 (d, 1H, J=7.2 Hz), 7.03 (t, 1H, J=7.9 Hz),
7.11 (t, 1H, J=7.9 Hz), 7.31 (d, 1H, J=2.3 Hz), 7.39 (d,
1H, J=7.9 Hz), 7.70 (d, 1H, J=7.9 Hz), 10.23 (brs, 1H).
10. Selected data for (S,S,R)-2: [h]2D2 −211 (c 0.89, CHCl3);
1H NMR (CDCl3): l −0.13 (s, 6H), 0.81 (s, 9H), 2.23
(brs, 2H), 3.26 (m, 2H), 3.70 (dd, 1H, J=11.1 and 8.0
Hz), 3.90 (m, 1H), 3.98 (d, 1H, J=11.1 Hz), 6.58 (brs,
1H), 7.05–7.25 (m, 3H), 7.37 (d, 1H, J=7.9 Hz), 7.51 (d,
1H, J=7.8 Hz), 8.93 (brs, 1H).
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