Concise syntheses of racemic and enantiopure deoxydysibetaine

Article abstract of DOI:10.1016/S0040-4039(03)01505-3

Racemic deoxydysibetaine was efficiently obtained in few steps from methyl pyroglutamate. The 2S enantiomer was synthesized from (S)-pyroglutaminol as chiral starting material, through the key intermediate (S)-2-hydroxymethylglutamic acid recently prepare

Full text of DOI:10.1016/S0040-4039(03)01505-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5961–5963
Concise syntheses of racemic and enantiopure deoxydysibetaine
Bao Khanh Le Nguyen and Nicole Langlois*
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 12 May 2003; revised 17 June 2003; accepted 17 June 2003
Abstract—Racemic deoxydysibetaine was efficiently obtained in few steps from methyl pyroglutamate. The 2S enantiomer was
synthesized from (S)-pyroglutaminol as chiral starting material, through the key intermediate (S)-2-hydroxymethylglutamic acid
recently prepared with complete stereoselectivity in our laboratory.
© 2003 Elsevier Ltd. All rights reserved.
studies. We designed deoxydysibetaine 2 as our first
synthetic target and here are reported the main results
in this field.
Dysibetaine 1 was isolated from an aqueous extract of
the marine sponge Dysidea herbacea collected in Yap,
Micronesia,1 beside an original non-NMDA glutamate
receptor agonist named dysiherbaine.2 The betaine 1 is
an a-amino acid a-substituted by a trimethylammo-
niomethyl group. The structure of 1 was established by
NMR and X-ray crystal analysis but its absolute
configuration (2S,4S) was assigned only two years later
by the sole total synthesis of the four diastereomers.3
The preparation of racemic 2 was envisioned from
pyroglutamic acid through
a
direct dimethyl-
aminomethylation at C-2. This key step was achieved
without protection of the nitrogen atom as carbamate,
to avoid a reaction at a position of the lactam
carbonyl.4
Accordingly, methyl pyroglutamate 3 was deprotonated
by 2.1 equiv. of base (LiHMDS in THF) and alkylated
with Eschenmoser salt at −60°C to afford the N,N-
dimethylaminomethyl derivative 4 in 82% yield (Scheme
1).
However, the isolation of 4 needed careful and rapid
extraction because the methyl ester function was shown
to be rather unstable and particularly sensitive to water.
Indeed, the ester was rapidly hydrolyzed by water at
room temperature, probably with the assistance of the
neighbouring amino group to give 6, as outlined in the
Scheme 2.
As dysibetaine is able to induce a convulsive behaviour
in mice, this compound was suspected of acting to
glutamate receptors in central nervous system.1 Thus,
the synthesis of simpler analogues could be interesting
for comparison purpose in further pharmacological
Scheme 1. Reagents and conditions: (a) LiHMDS, THF, Eschenmoser salt, 82%; (b) CH3I, THF, 78%; (c) Dowex 550A, HO−,
85%.
* Corresponding author. Fax: +33-1-6907-7247; e-mail: nicole.langlois@icsn.cnrs-gif.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01505-3

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B. K. Le Nguyen, N. Langlois / Tetrahedron Letters 44 (2003) 5961–5963
Scheme 2.
The compound 4 in THF was then converted into the
trimethylammonium iodide 5 with an excess of methyl
iodide under standard conditions (78%). The treatment
of 5 with Dowex 550A resin in the hydroxide form (in
methanol at 55°C)3 allowed to obtain racemic deoxy-
dysibetaine ( )-2 in 85% yield (Scheme 1).
of diazomethane employed but especially to the pres-
ence of methanol in this methylation to increase the
solubility of the starting product.8 Formation of the
aminomethyl group at C-2 by reductive amination9 of
either aldehyde 10 or N-Boc protected 11, both
obtained with Dess–Martin reagent,10 gave disappoint-
ing results.
Next, the synthesis of the enantiomer (2S)-2 (the
configuration of natural dysibetaine 1 at C-2) was
planned as described in the Scheme 3.
Thus, an alternative classical route was investigated
(Scheme 3). Mesylation of the primary alcohol 8 (MsCl,
CH2Cl2–Et3N, 0°C) gave the mesylate 12 (86%) which
was substituted with NaN3 at 65°C providing the azi-
domethyl derivative 13 in 91% yield. The compound 13
was quantitatively reduced with hydrogen and Pd–10%/
C as catalyst. The resulting primary amine 14, charac-
terized as its hydrochloride, was dimethylated with
aqueous formol under hydrogen (Pd–10%/C, 40–50 psi)
giving rise to (S)-4 (64%), which was in turn converted
into trimethylammonium iodide (S)-5 according a com-
mon protocol (86%, Scheme 3).3,11 It is worthy of note
that the same intermediate (S)-5 could be obtained also
by a more direct and more efficient way (94%) from the
aminomethyl derivative 14, provided that diisopropyl-
ethylamine was added to the reaction with methyl
iodide in excess. This 2-methoxycarbonyl-2-trimethyl-
This synthesis started from (S)-2-hydroxymethylglu-
tamic acid hydrochloride 7, recently synthesized in our
laboratory with complete stereoselectivity.5 This amino
diacid failed to provide 2-hydroxymethylpyroglutamic
acid by lactamization under mild conditions, after the
displacement of the hydrochloride with triethylamine.
Thus, the diacid was methylated with trimethylsilyldia-
zomethane or more simply with diazomethane in excess
(in a mixture of MeOH–Et2O) to afford directly the
methyl (S)-2-hydroxymethylpyroglutamate 8 in 67%
yield.6 Some amounts (10%) of a side product 9 result-
ing from nitrogen methylation was also isolated, but
the formation of lactim ether was not observed.7 The
N-methylation of 8 could be due not only to the excess
Scheme 3. Reagents and conditions: (a) CH2N2, MeOH–Et2O, 67%; (b) MsCl, CH2Cl2, Et3N, 86%; (c) NaN3, DMF, 65°C, 91%;
(d) H2, Pd–10%/C, MeOH, 100%; (e) CH2O, H2 40–50 psi, Pd–10%/C, 64%; (f) CH3I, THF, 86%; (g) CH3I, EtN(iPr)2, THF,
94%); (h) Dowex 550A, HO−, 100%.

B. K. Le Nguyen, N. Langlois / Tetrahedron Letters 44 (2003) 5961–5963
5963
ammoniomethylpyrrolidin-5-one was hydrolyzed quan-
titatively into deoxydysibetaine (S)-2, as described
above for the racemic counterpart.12
Tetrahedron Lett. 2003, 43, 463–464.
6. Andrews, M. D.; Brewster, A. G.; Moloney, M. G.;
Owen, K. L. J. Chem. Soc., Perkin Trans. 1 1996, 227–
228.
In conclusion, two simple routes were developed to
prepare racemic and enantiopure deoxydysibetaine
respectively, in high yields. The synthesis of further
analogues of dysibetaine is currently under investiga-
tion.
7. Nishiyama, H.; Nagase, H.; Ohno, K. Tetrahedron Lett.
1979, 20, 4671–4674.
8. Ralls, J. W. J. Org. Chem. 1961, 26, 66–68.
9. Berdini, V.; Cesta, M. C.; Curti, R.; D’Anniballe, G.; Di
Bello, N.; Nano, G.; Nicolini, L.; Topai, A.; Allegretti,
M. Tetrahedron 2002, 58, 5669–5674 and references cited
therein.
10. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48,
4155–4156; (b) Dess, D. B.; Martin, J. C. J. Am. Chem.
Soc. 1991, 113, 7277–7287; (c) Ireland, R. E.; Liu, L. J.
Org. Chem. 1993, 58, 2899.
Acknowledgements
We are grateful to Professor J.-Y. Lallemand, Director
of ICSN for a grant (B.K.L.N.).
11. (a) Jain, R. P.; Williams, R. M. Tetrahedron Lett. 2001,
42, 4437–4440; (b) Jain, R. P.; Williams, R. M. Tetra-
hedron 2001, 57, 6505–6509.
References
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12. Data of (S)-2: Mp: 226°C; [h]2D4=−9 (c 0.84, MeOH). H
NMR (300 MHz, D2O l=4.65 ppm): 3.92 (d, 1H, J=15
Hz, Ha-6), 3.56 (d, 1H, J=15 Hz, Hb-6), 3.08 (s, 9H,
N(CH3)3), 2.41 (m, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 2.04
(m, 1H): H2-4, H2-3. 13C NMR (75.0 MHz, CD3OD
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