Biologically interesting chiral 3,4-disubstituted pyrrolidines from optically active hydroxycitric acid lactones

Article abstract of DOI:10.1016/S0040-4039(02)02781-8

Starting with (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (garcinia acid), isolated from the chiral pool, and alkyl amines, 3,4-disubstituted pyrrolidinediones, analogues of naturally occurring mescaline isocitrimidelactone, have been obtained in one-pot. These imides were subsequently converted into optically active pyrrolidines.

Full text of DOI:10.1016/S0040-4039(02)02781-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1247–1249
Biologically interesting chiral 3,4-disubstituted pyrrolidines from
optically active hydroxycitric acid lactones
Ibrahim Ibnusaud* and Grace Thomas
School of Chemical Sciences, Mahatma Gandhi University, P. D. Hills PO, Kottayam, Kerala 686560, India
Received 24 October 2002; revised 29 November 2002; accepted 6 December 2002
Abstract—Starting with (2S,3S)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid (garcinia acid), isolated from the chiral
pool, and alkyl amines, 3,4-disubstituted pyrrolidinediones, analogues of naturally occurring mescaline isocitrimidelactone, have
been obtained in one-pot. These imides were subsequently converted into optically active pyrrolidines. © 2003 Elsevier Science
Ltd. All rights reserved.
Chiral pyrrolidines are common structural subunits
found in a variety of natural and unnatural bioactive
products.1 Depending on the substitution pattern and
functionality, pyrrolidines have been shown to be effec-
tive antibacterials, neuroexcitatory agents, potent ven-
oms, glycosidase inhibitors and fungicides.2 Numerous
biological compounds possess pyrrolidine rings as their
framework and some of them are pharmaceutically
important. In addition, enantiomerically pure pyrrolidi-
nes are also useful chiral auxiliaries.3 Hence, prepara-
tion of enantiopure polysubstituted pyrrolidine
derivatives is quite a challenging subject. A number of
stereoselective methods for the synthesis of 2,5-disubsti-
tuted pyrrolidines have been reported during the last
decade.4 These include cyclisation of bis-allylic amines,
1,3-dipolar cycloaddition, reduction–cyclisation of g-
aza derivatives of ketones, synthesis from aza heterocy-
cles etc. Nonetheless, general and effective methods for
the selective synthesis of 3,4-polysubstituted pyrrolidi-
nes are noticeably rare.5 Since a number of natural
products containing pyrrolidines with this specific sub-
stitution pattern are of particular interest, a search for
improved methods for their preparation is warranted.
This communication reports a simple synthesis of chiral
3,4-disubstituted pyrrolidines from optically active
hydroxycitric acid lactones.
1960s, and can be easily isolated from natural sources
following our recently reported methods,7 no efforts
have been made to explore them as potential synthons
in organic synthesis (Fig. 1).
Figure 1.
When 1 is successively treated with acetyl chloride,
appropriate amines and acetyl chloride, cyclic imides
4a–d are obtained in good yields. From Garcinia acid
dimethylester 3, imides 4a%–d% were obtained by reflux-
ing with appropriate amines in toluene (Scheme 1). The
Chiral hydroxy acids such as malic acid and tartaric
acid have been extensively employed for the construc-
tion of nitrogen heterocycles like pyrrolidines,
pyrrolizidine alkaloids etc.6 Though optically active
hydroxy acids namely Garcinia acid
diastereomer Hibiscus acid 2 have been known since the
1 and its
* Corresponding author. Tel.: +91-481-731036; fax: +91-481-731009;
e-mail: i ibnu@yahoo.co.in
Figure 2.
–
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02781-8

1248
I. Ibnusaud, G. Thomas / Tetrahedron Letters 44 (2003) 1247–1249
Scheme 1.
IR, 1H and 13C NMR spectra clearly indicate the
presence of g-butyrolactone and cyclic imide moieties.9
The imides were further reduced with LAH followed by
refluxing with acetyl chloride to give 3,4-disubstituted
pyrrolidines 5a–d.
endangered species with very low active principle
content8 (Fig. 2).
When the experiment is repeated with hibiscus acid 2,
or its ester 6 and alkyl amines, no cyclic imide is formed
as the expected product 8 would be trans fused. Instead,
mono amides 7a to 7d were isolated in good yields
(Scheme 2).
It is interesting to note that cyclic imides 4d and 4d% are
analogues of the less well known mescaline isocitrimide
lactone 9, a psychotic bioprinciple obtained from mes-
cal (Lophophora williamsii ) a rare and very slow grow-
ing solitary cactus, which is also classified as an
Further use of 4, 5 and 7 for the synthesis of biologi-
cally interesting molecules is underway.
Scheme 2.

I. Ibnusaud, G. Thomas / Tetrahedron Letters 44 (2003) 1247–1249
1249
Acknowledgements
7. (a) Ibnusaud, I.; Thomas, T. P.; Rani, R. N.; Sasi, P. V.;
Beena, T.; Hisham, A. K. Tetrahedron 2002, 58, 4887–4892
and references cited therein; (b) Ibnusaud, I.; Thomas, T.
P.; Thomas, B. US Patent no. 6,147, 228; Indian patent
application no. 2248/Del/98,1998; (c) Ibnusaud, I.; Nair,
R. R.; Philip, T.; Thomas, S. US Patent no. 6,127,553;
Indian patent application no. 2249/Del/98,1998; (d) Jena,
B. S.; Jayaprakasha, G. K.; Sing, R. P.; Sakaria, K. K. J.
Agric. Food Chem. 2002, 50, 10–22.
8. (a) Southon, I. W.; Buckingham, J. Dictionary of Alka-
loids: Chapman and Hall Ltd. 1989, p. 694; (b) Kapadia,
G. J.; Fayez, M. B. E. J. Pharm. Sci. 1970, 59, 1699–1725.
9. General procedure for the synthesis of a representative
example (4a) and its spectral data.
This work was financially supported by the Department
of Science and Technology vide project no: SP/S1/G-
07/95/PRU. The authors thank SIF, I.I.Sc., Bangalore
for recording the NMR spectra CDRI, Lucknow for
obtaining the mass spectra and elemental analysis data,
RRL, Trivandrum for measuring the optical rotation
values.
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